Lecture 14 - Immunology Study Guide PDF

T cell activation T cell activation is a critical process in the adaptive immune response that occurs following the recognition of antigens presented by antigen-presenting cells (APCs). Here's an overview of the key stages of T cell activation and the subsequent generation of effector and memory T c...

T cell activation T cell activation is a critical process in the adaptive immune response that occurs following the recognition of antigens presented by antigen-presenting cells (APCs). Here's an overview of the key stages of T cell activation and the subsequent generation of effector and memory T cells: 1.Recognition of Antigen: 1. T cell activation begins when a T cell receptor (TCR) on the surface of a T cell binds to a specific antigen peptide presented by major histocompatibility complex (MHC) molecules on the surface of APCs. 2. This interaction is facilitated by co-stimulatory molecules such as CD28 on the surface of T cells and CD80/CD86 on the surface of APCs. 2.Clonal Expansion: 1. Upon antigen recognition and co-stimulation, the activated T cell undergoes clonal expansion. 2. Clonal expansion involves the rapid proliferation of the activated T cell, leading to the generation of a large number of effector T cells with identical antigen specificity. 3. This expansion phase allows the immune system to mount a robust and specific response against the invading pathogen. 3.Effector Cell Differentiation: 1 1. During clonal expansion, activated T cells differentiate into effector T cells with specialized functions. 2. CD4+ T cells differentiate into various subsets such as T helper 1 (Th1), Th2, Th17, or regulatory T (Treg) cells, depending on the cytokine milieu and signals received during activation. 3. CD8+ T cells differentiate into cytotoxic T lymphocytes (CTLs) capable of directly killing infected or abnormal cells. 1.Contraction (Homostasis): 1. Following the peak of the immune response, the number of effector T cells declines through a process known as contraction or homostasis. 2. During contraction, the majority of effector T cells undergo apoptosis, reducing their numbers to pre-infection levels. 3. This phase helps to prevent excessive immune activation and tissue damage. 2.Memory T Cell Generation: 1. A subset of activated T cells survives the contraction phase and differentiates into long-lived memory T cells. 2. Memory T cells possess enhanced responsiveness to antigen re-exposure and provide immunological memory. 3. Memory T cells can rapidly proliferate and differentiate into effector T cells upon encountering the same antigen during a secondary infection, leading to a faster and more robust immune response. In summary, T cell activation involves a series of coordinated events, including clonal expansion, effector cell differentiation, contraction, and memory T cell generation. These processes are crucial for mounting an effective immune response against pathogens and providing long-term immunity to prevent reinfection. 1 T cell life history events HSCs Naïve T cells Activated T cells Effector T cells & Memory T cells Memory T cells Certainly! The life history of T cells encompasses various stages, from their development from hematopoietic stem cells (HSCs) to their role in the adaptive immune response as effector and memory cells. Let's delve into each stage in detail: 1.Hematopoietic Stem Cells (HSCs): 1. T cell development begins in the bone marrow, where hematopoietic stem cells (HSCs) differentiate into progenitor cells committed to the lymphoid lineage. 2. These progenitor cells migrate to the thymus, where they undergo further maturation into naïve T cells. 2.Naïve T Cells: 1. Naïve T cells are mature T cells that have not yet encountered their cognate antigen. 2. These T cells express a diverse repertoire of T cell receptors (TCRs) capable of recognizing specific antigens presented by major histocompatibility complex (MHC) molecules. 3. Naïve T cells circulate through the blood and lymphoid tissues, constantly surveying for antigens. 3.Activation of T Cells: 1. Upon encountering their cognate antigen presented by antigen- 2 presenting cells (APCs), such as dendritic cells, naïve T cells become activated. 2. T cell activation involves the binding of the TCR to the antigen-MHC complex and co-stimulatory signals provided by molecules such as CD28 and CD80/86. 3. Activated T cells undergo proliferation and differentiation into effector T cells, which mediate various functions in the immune response. 1.Effector T Cells and Memory T Cells: 1. Effector T cells are the immediate responders to antigen encounter and are specialized for specific functions. 2. CD4+ effector T cells can differentiate into subsets such as T helper 1 (Th1), Th2, Th17, or regulatory T (Treg) cells, depending on the cytokine milieu. 3. CD8+ effector T cells, also known as cytotoxic T lymphocytes (CTLs), directly kill infected or abnormal cells. 4. Memory T cells are a long-lived subset of T cells that arise during the primary immune response and persist after antigen clearance. 5. Memory T cells exhibit rapid recall responses upon re-encountering the same antigen, leading to a faster and more robust secondary immune response. 2.Contraction and Maintenance of Memory: 1. After the peak of the immune response, the population of effector T cells declines through a process called contraction. 2. The majority of effector T cells undergo apoptosis, while a small fraction survives and differentiates into long-lived memory T cells. 3. Memory T cells persist in the body for an extended period, providing immunological memory and protection against reinfection. In summary, the life history of T cells involves a series of stages, from development in the bone marrow to activation, differentiation into effector cells, contraction, and generation of memory cells. These processes are essential for mounting effective immune responses against pathogens and providing long-term immunity. 2 Activation of naïve and effector T cells by antigen Lymphocytes respond to antigen at two points in their life history Antigen-presenting cells (APCs) play a crucial role in initiating and regulating immune responses by presenting antigens to T cells. Here's a detailed explanation of what APCs do and how they activate naïve and effector T cells: 1.Antigen Presentation: 1. APCs capture antigens from pathogens, such as bacteria or viruses, through processes such as phagocytosis or endocytosis. 2. Once inside the APC, antigens are processed into peptide fragments. 3. These peptide fragments are then loaded onto major histocompatibility complex (MHC) molecules, which serve as molecular platforms for presenting antigens to T cells. 4. APCs can express both MHC class I molecules (presenting endogenous antigens to CD8+ T cells) and MHC class II molecules (presenting exogenous antigens to CD4+ T cells). 2.Signal Provision: 1. In addition to antigen presentation, APCs provide signals that guide T cell responses. 2. Co-stimulatory molecules, such as CD80 (B7.1) and CD86 (B7.2), on the surface of APCs interact with CD28 receptors on T cells to provide a crucial second signal for T cell activation. 3 3. Without co-stimulation, T cell activation may be aborted, leading to tolerance rather than an immune response. 4. Cytokines secreted by APCs also influence T cell activation and differentiation. For example, dendritic cells can produce interleukin-12 (IL-12), which promotes the differentiation of naïve CD4+ T cells into Th1 cells. 1.Activation of Naïve T Cells: 1. Naïve T cells continuously circulate through secondary lymphoid organs such as lymph nodes, where they survey APCs for antigen presentation. 2. When a naïve T cell encounters an APC presenting its cognate antigen peptide-MHC complex along with co-stimulatory signals, it becomes activated. 3. This activation leads to clonal expansion and differentiation of the naïve T cell into effector T cells, which mediate immune responses against the antigen. 2.Activation of Effector T Cells: 1. Effector T cells, which are already primed and circulating in the bloodstream or lymphoid tissues, can also be activated by APCs presenting antigens. 2. This activation occurs when effector T cells encounter APCs presenting antigens that match their TCR specificity. 3. The interaction between the TCR on the effector T cell and the peptideMHC complex on the APC, along with co-stimulatory signals, reinforces T cell activation and promotes effector functions such as cytokine production or cytotoxicity. In summary, APCs play a central role in immune responses by capturing, processing, and presenting antigens to T cells. Through antigen presentation and provision of costimulatory signals and cytokines, APCs activate both naïve and effector T cells, initiating and regulating adaptive immune responses against pathogens and foreign antigens. 3 Sequence of events in T cell responses Numerous cytokines drive the progression APCs Express both MHC II & MHC I Display antigen Provide signals that guide T cell response => Costimulators & Cytokines ChatGPT ChatGPT The sequence of events in T cell responses involves a series of coordinated interactions between antigen-presenting cells (APCs), T cells, and other immune cells. Here's a detailed explanation of the key steps in the T cell response: 1.Antigen Presentation by APCs: 1. Antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B cells, capture antigens from pathogens or infected cells. 2. APCs process these antigens into peptide fragments and present them on their cell surface using major histocompatibility complex (MHC) molecules. 3. APCs express both MHC class I molecules (presenting endogenous antigens to CD8+ T cells) and MHC class II molecules (presenting exogenous antigens to CD4+ T cells). 2.Activation of Naïve T Cells: 1. Naïve T cells continuously circulate through secondary lymphoid organs, such as lymph nodes, where they encounter APCs presenting antigens. 2. When a naïve T cell recognizes its cognate antigen presented by an APC, 4 along with co-stimulatory signals provided by molecules such as CD80/CD86, it becomes activated. 3. This activation leads to the clonal expansion and differentiation of naïve T cells into effector T cells with specialized functions. 1.Effector Functions of T Cells: 1. Activated effector T cells migrate to sites of infection or inflammation, where they exert their effector functions. 2. CD4+ T helper (Th) cells release cytokines to activate and recruit other immune cells, such as macrophages, B cells, and cytotoxic T cells, to eliminate pathogens. 3. Th1 cells produce interferon-gamma (IFN-gamma) to activate macrophages, enhancing their ability to kill intracellular pathogens. 4. Th2 cells secrete cytokines such as interleukin-4 (IL-4) and interleukin-5 (IL-5) to promote antibody production by B cells and the elimination of extracellular parasites. 5. Cytotoxic CD8+ T cells directly kill infected or abnormal cells by releasing cytotoxic molecules such as perforin and granzymes. 2.Resolution of Infection and Tissue Repair: 1. As the immune response progresses, effector T cells, along with other immune cells, work together to eliminate the pathogen and resolve the infection. 2. Regulatory T cells (Tregs) help to dampen excessive immune responses and prevent tissue damage caused by inflammation. 3. Once the infection is cleared, the majority of effector T cells undergo apoptosis, while a small fraction differentiates into long-lived memory T cells. 3.Memory T Cell Formation: 1. Memory T cells persist in the body after the resolution of infection and provide immunological memory. 2. Memory T cells are poised to rapidly respond to re-infection with the same pathogen, leading to a faster and more robust secondary immune response. In summary, the sequence of events in T cell responses involves antigen presentation by APCs, activation of naïve T cells, effector functions mediated by activated T cells, resolution of infection, and the formation of memory T cells. These processes are essential for effective immune responses against pathogens and the maintenance of long-term immunity. 4 Cytokines typically “tell” the responding cell to ______________. A. alter expression of certain genes B. begin chemotaxis C. undergo apoptosis D. suppress metabolic activity ChatGPT ChatGPT Cytokines typically "tell" the responding cell to alter the expression of certain genes. Cytokines are signaling molecules produced by various immune cells, including T cells, B cells, macrophages, and dendritic cells, among others. When released, cytokines bind to specific receptors on the surface of target cells, triggering intracellular signaling pathways that lead to changes in gene expression. These changes can influence a wide range of cellular processes, including proliferation, differentiation, migration, and activation. Therefore, cytokines play critical roles in modulating immune responses, inflammation, and various physiological processes by regulating gene expression in target cells. 5 Costimulators are important for T cell activation Certainly! Costimulatory signals are indeed crucial for T cell activation, and they play essential roles in regulating immune responses. Let's explore each scenario in detail: Scenario A: In the absence of costimulatory signals, T cell activation may not occur, or the T cell may become tolerant to the antigen. For instance, if an antigen-presenting cell (APC) presents a self-antigen to a T cell without providing costimulatory signals, the T cell may not respond or may even become tolerant to the self-antigen. One of the key costimulatory molecules involved in T cell activation is CD28, which is expressed on the surface of T cells. CD28 interacts with CD80 (B7.1) and CD86 (B7.2) molecules on the surface of APCs to provide a crucial second signal for T cell activation. Therefore, the presence or absence of costimulatory signals, such as CD28-B7 interactions, can determine whether a T cell becomes activated or tolerant to the antigen presented by the APC. Scenario B: When an APC encounters microbial pathogens or activates innate immune responses, it increases the expression of costimulatory molecules, such as CD80 and CD86. 6 This upregulation of costimulatory molecules enhances the ability of the APC to provide costimulatory signals to T cells during antigen presentation. Additionally, innate immune responses triggered by microbial pathogens can lead to the production of proinflammatory cytokines, such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). These cytokines further stimulate the expression of costimulatory molecules on APCs and promote T cell activation and differentiation. Upon activation by APCs presenting antigens and providing costimulatory signals, T cells upregulate the expression of interleukin-2 (IL-2) and its receptor (IL-2R). IL-2 plays a critical role in T cell survival, proliferation, and differentiation into effector T cells. It promotes the expansion of activated T cells and supports their effector functions. Scenario C: Cytokines secreted by various immune cells, including T cells, APCs, and other leukocytes, play important roles in modulating immune responses. Among these cytokines, interleukin-2 (IL-2) is particularly important for T cell activation and proliferation. IL-2 is produced primarily by activated T cells themselves, particularly CD4+ helper T cells. It acts in an autocrine and paracrine manner to stimulate the proliferation and differentiation of T cells. IL-2 signaling through its receptor (IL-2R) promotes T cell survival, expansion, and differentiation into effector T cells, which mediate immune responses against pathogens. In summary, costimulatory signals provided by APCs, along with proinflammatory cytokines and IL-2 produced during immune responses, are critical for T cell activation, proliferation, and differentiation into effector T cells. These signals orchestrate the adaptive immune response and help regulate the magnitude and duration of immune responses against pathogens. 6 Costimulators in APCT cell interactions Expressed in response to microbial products and various cytokines Certainly! Costimulatory molecules play crucial roles in regulating T cell activation and function during immune responses. Let's delve into the details of the key costimulators and their functions: 1.B7/CD28 Pathway: 1. B7 molecules (CD80 and CD86) are expressed on the surface of antigenpresenting cells (APCs) in response to microbial products and various cytokines. 2. When APCs present antigens to T cells, they also express B7 molecules, which interact with the CD28 receptor on T cells. 3. CD28-B7 interactions provide essential costimulatory signals that enhance T cell activation, proliferation, and differentiation into effector T cells. 4. CD28 engagement promotes the production of interleukin-2 (IL-2) and the expression of other cytokines necessary for T cell activation and function. 5. Regulatory T cells (Tregs) also express CD28, which is involved in their activation and suppressive functions. 2.CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4): 1. CTLA-4 is structurally similar to CD28 and competes with CD28 for 7 binding to B7 molecules on APCs. 2. Unlike CD28, which promotes T cell activation, CTLA-4 acts as a negative regulator of T cell activation. 3. CTLA-4 is upregulated on activated T cells, including naïve T cells, and functions to dampen immune responses. 4. When CTLA-4 engages with B7 molecules, it sends inhibitory signals that suppress T cell activation and proliferation. 5. The inhibitory function of CTLA-4 helps prevent excessive or prolonged immune responses and maintains immune homeostasis. 1.PD-1 (Programmed Cell Death Protein 1): 1. PD-1 is another inhibitory receptor expressed on activated T cells, primarily effector T cells, upon antigen encounter. 2. PD-1 interacts with its ligands, PD-L1 (programmed death-ligand 1) and PD-L2, which are expressed on the surface of APCs and other cells. 3. Binding of PD-1 to its ligands delivers inhibitory signals that dampen T cell activation and effector functions. 4. PD-1 signaling is crucial for regulating immune responses and preventing excessive tissue damage and autoimmunity. 5. However, PD-1 can also be exploited by pathogens and tumors to evade immune surveillance by suppressing T cell responses. In summary, costimulatory molecules such as CD28 provide essential signals for T cell activation and effector functions, while inhibitory receptors like CTLA-4 and PD-1 serve as checkpoints to regulate immune responses and maintain immune tolerance. The balance between costimulatory and inhibitory signals is critical for modulating the magnitude and duration of immune responses and preventing immune-related disorders. 7 Manipulation of the B7/CD28 interaction for therapeutic purposes Normal signaling Recombinant “drug” ChatGPT 3.5 You A trade-off for having many offspring would be Group of answer choices that they would likely be large in size that they would likely be small in size that they would have high survivorship that they would require a large amount of parental care Flag question: Question 2 Question 21 pts In a population exhibiting logistic growth, for very low values of N relative to K, the population will grow almost Group of answer choices exponentially at 3/4 power at a rate = 1- K at a rate = K bold correct answers 2/2 ChatGPT ChatGPT A trade-off for having many offspring would be that they would require a large amount of parental care. In a population exhibiting logistic growth, for very low values of N relative to K, the population will grow almost exponentially. You As the density of a population increases, the Group of answer choices individual reproduction rate increases individual growth rate decreases intensity of intraspecific competition decreases individual survival rate increases Flag question: Question 4 8 Question 41 pts The portion of potential resources and conditions that an organism actually takes advantage of in the presence of competitors is called the ________ of that organism. Group of answer choices fundamental niche territory realized niche home range ChatGPT ChatGPT As the density of a population increases, the intensity of intraspecific competition increases. The portion of potential resources and conditions that an organism actually takes advantage of in the presence of competitors is called the realized niche. You The process whereby one species gives rise to several others that exploit different features of the environment is known as Group of answer choices coevolution exponential growth competition adaptive radiation Flag question: Question 6 Question 61 pts Based on the logistic growth equation, the ideal number of fish to catch to provide the most yield while sustaining fisheries is Group of answer choices = dN/dt = rN(1- N/K ) at K at K/2 ChatGPT ChatGPT The process whereby one species gives rise to several others that exploit different features of the environment is known as adaptive radiation. Based on the logistic growth equation, the ideal number of fish to catch to provide the most yield while sustaining fisheries is at K/2. You An r-strategist is characterized by Group of answer choices density-dependent mortality density-independent mortality slow population growth a long life expectancy Flag question: Question 8 Question 81 pts If N(0) = 30 and λ = 1.20, what is the population size for year one? Group of answer choices 3.6 2.5 25 36 Flag question: Question 9 Question 91 pts The invasive species, Snakehead, has been introduced to the New River and sampled in Pulaski County. Local biologists are very concerned due to the Snakehead’s limited predators and abundant supply of food in the New River. What type of population curve should biologist predict? Group of answer choices Exponential Zero Growth Slow Growth Logistic ChatGPT ChatGPT An r-strategist is characterized by density-independent mortality. For question 8, if N(0) = 30 and λ = 1.20, the population size for year one can be calculated using the equation N(t) = N(0) * λ^t. Substituting the values, N(1) = 30 * 1.20^1 = 36. For question 9, given the invasive species Snakehead with limited predators and abundant food supply in the New River, biologists should predict an Exponential population curve. 8 You Save & Submit Cancel ChatGPT ChatGPT A trade-off for having many offspring would be that they would require a large amount of parental care. You d is not the correct answer ChatGPT ChatGPT I see, let's reconsider. A trade-off for having many offspring would likely be that they would likely have small size. You As the density of a population increases, the Group of answer choices individual survival rate increases individual growth rate decreases intensity of intraspecific competition decreases individual reproduction rate increases Flag question: Question 4 ChatGPT ChatGPT As the density of a population increases, the intensity of intraspecific competition increases. You it is not increase ChatGPT ChatGPT Apologies for the oversight. Let's correct that. As the density of a population increases, the individual reproduction rate decreases. You Lymphocyte maturation involves: Commitment of progenitor cells to either the B lymphoid or T lymphoid lineage Proliferation of progenitor cells and immature committed cells Sequential rearrangement (recombination) of antigen receptor chains Selection of cells expressing functional antigen receptors & elimination of cells that strongly recognize self antigens Differentiation of B and T cells into distinct subpopulations explain in detail ChatGPT ChatGPT Lymphocyte maturation is a complex process that involves several key steps in the development of B and T lymphocytes, two types of white blood cells that play crucial roles in the immune system. 1.Commitment of progenitor cells to either the B lymphoid or T lymphoid lineage: 8 Initially, hematopoietic stem cells in the bone marrow differentiate into progenitor cells that are committed to the lymphoid lineage. These progenitor cells then undergo further specialization to become either B lymphoid progenitors or T lymphoid progenitors. This commitment is driven by specific transcription factors and signaling pathways that guide the cells towards either B cell or T cell development. 2. Proliferation of progenitor cells and immature committed cells: Once committed to either the B or T cell lineage, the progenitor cells undergo rapid proliferation. This proliferation phase expands the population of cells committed to lymphocyte development, ensuring a sufficient pool of cells for subsequent stages of maturation. During this phase, the cells undergo extensive cell division to increase their numbers. 3.Sequential rearrangement (recombination) of antigen receptor chains: In both B and T cell development, a critical step is the rearrangement of genes encoding the antigen receptor chains. In B cells, this involves the rearrangement of the genes encoding the immunoglobulin heavy and light chains, while in T cells, it involves the rearrangement of genes encoding the T cell receptor (TCR) chains. This rearrangement process, known as V(D)J recombination, generates diverse antigen receptor molecules with unique specificities for recognizing a wide range of foreign antigens. 4.Selection of cells expressing functional antigen receptors & elimination of cells that strongly recognize self-antigens: Following rearrangement of the antigen receptor genes, immature B and T cells undergo a process of selection to ensure that they express functional receptors capable of recognizing foreign antigens while avoiding recognition of self-antigens. In the bone marrow, immature B cells that express autoreactive receptors undergo negative selection, leading to their elimination via apoptosis. Similarly, in the thymus, immature T cells undergo positive selection, where they must demonstrate the ability to recognize self-major histocompatibility complex (MHC) molecules, and those that fail to do so undergo apoptosis. This process helps to prevent the development of autoimmune responses while promoting the generation of functional lymphocytes capable of mounting effective immune responses against pathogens. 5.Differentiation of B and T cells into distinct subpopulations: Once matured and released into the peripheral circulation, B and T cells further differentiate into distinct subpopulations with specialized functions. For example, B cells may differentiate into plasma cells, which produce antibodies, while T cells may differentiate into helper T cells, cytotoxic T cells, or regulatory T cells, each with specific roles in immune responses. Overall, lymphocyte maturation involves a highly regulated series of events that ensure the generation of diverse, functional lymphocytes capable of recognizing and responding to a wide range of pathogens while maintaining self-tolerance. You Selection and Elimination Occurs at Checkpoints Cells that fail to meet requirements of checkpoint will undergo apoptosis proliferation- means more cells First check 8 point( pre-b/t receptor expression- does this occur cells that pass this check point will prolifeate again and go to Checkpoint 2 and the cells are immature or mature cells and this means they made 2 chains and if not and only made one tat means cells experenice cells death Checkpoint1: is first chain functional? Checkpoint 2: is complete receptor functional? Only functional( all about the function) receptors deliver signals to developing lymophcytes - only lymphocytes that produce functional receptors will survive Most likely reason for a nonfuctional polypeptide chain is an out of frame gene rearrangement (will occur two out of three rearrangement) explain in detail ChatGPT ChatGPT Certainly, let's break down the process of lymphocyte maturation and the checkpoints in detail: 1.Pre-B/T Receptor Expression Checkpoint (Checkpoint 1): 1. This checkpoint occurs during the early stages of B and T lymphocyte development. 2. For B cells, the pre-B cell receptor consists of a surrogate light chain (composed of VpreB and λ5 proteins) associated with the Ig-α and Ig-β signaling molecules. 3. For T cells, the pre-T cell receptor consists of a pre-TCR complex containing the TCRβ chain associated with the pre-Tα chain. 4. Cells that successfully assemble the pre-B or pre-T cell receptor pass this checkpoint and proceed to proliferate. 5. Cells that fail to assemble a functional pre-receptor undergo apoptosis. 2.First Chain Functional Checkpoint (Checkpoint 2): 1. This checkpoint occurs after the successful assembly of the first chain (either heavy or β chain) of the B or T cell receptor. 2. At this stage, the cell undergoes proliferation and further differentiation. 3. For B cells, successful assembly of the heavy chain leads to the expression of the IgM molecule on the cell surface. 4. For T cells, successful assembly of the β chain leads to the expression of the pre-TCR complex. 5. Cells that fail to assemble a functional first chain undergo apoptosis. 3.Complete Receptor Functional Checkpoint: 1. This checkpoint occurs after the successful assembly of both chains (heavy and light for B cells, α and β for T cells) of the B or T cell receptor. 2. The fully assembled receptors undergo testing to ensure functionality. 3. Only cells expressing a complete and functional receptor are allowed to survive and continue their maturation process. 4. Cells with non-functional receptors undergo apoptosis. 4.Reasons for Non-functional Polypeptide Chain: 1. An out-of-frame gene rearrangement is a common reason for non- 8 functional polypeptide chains. 2. During V(D)J recombination, the variable (V), diversity (D, in the case of heavy chain), and joining (J) gene segments are rearranged to generate a diverse repertoire of antigen receptor genes. 3. If the rearrangement process results in an out-of-frame insertion or deletion of nucleotides, it disrupts the reading frame and leads to the production of a non-functional polypeptide chain. 4. Cells with non-functional chains typically fail to express a complete and functional receptor and are eliminated through apoptosis. Overall, these checkpoints ensure that only lymphocytes with functional antigen receptors are allowed to survive and participate in the immune response, while those with non-functional receptors are eliminated to maintain the integrity and effectiveness of the immune system. You Selection and Elimination Occurs at Checkpoints Cells with functional antigen receptor next subjected to: 1. Positive selection: promotes survival of potentially useful cells thought to depend on weak interaction with self antigen promotes maturation of t cells and survival of B cells 2. Negative selection eliminates t cells bind strongly to self antigens - clonal deletion But B cells may undergo further rearrangements ---> receptor editing This has to do. With the checkpoint of recongzing a self antigen Stronger reaction to a weaker reaction explain in detail ChatGPT ChatGPT Certainly, let's delve into the processes of positive selection, negative selection, and receptor editing in the context of lymphocyte maturation: 1.Positive Selection: 1. Positive selection is a crucial step in the maturation of T cells in the thymus and B cells in the bone marrow. 2. This process promotes the survival of lymphocytes that express antigen receptors capable of weakly interacting with self-antigens presented by the thymic epithelial cells (for T cells) or stromal cells (for B cells). 3. Positive selection ensures that T cells with TCRs capable of recognizing self-major histocompatibility complex (MHC) molecules and B cells with BCRs capable of recognizing self-antigens are allowed to mature and exit the thymus or bone marrow, respectively. 4. Positive selection is essential for the development of a diverse repertoire of functional lymphocytes capable of recognizing a wide range of foreign antigens while maintaining self-tolerance. 2.Negative Selection: 1. Negative selection, also known as central tolerance, is a critical mechanism for eliminating autoreactive lymphocytes that recognize selfantigens too strongly. 8 2. In the thymus, T cells that bind strongly to self-peptide-MHC complexes presented by thymic epithelial cells undergo apoptosis, a process known as clonal deletion. 3. In the bone marrow, immature B cells that express BCRs with high affinity for self-antigens are also eliminated through apoptosis. 4. Negative selection helps to prevent the development of autoimmune diseases by removing potentially harmful autoreactive lymphocytes from the repertoire. 1.Receptor Editing (B cells): 1. In some cases, immature B cells in the bone marrow may encounter selfantigens and undergo receptor editing to modify their antigen receptor specificity. 2. Receptor editing involves further rearrangements of the immunoglobulin genes to generate a new BCR with reduced affinity for self-antigens. 3. This process allows the B cell to escape negative selection and continue its maturation process. 4. Receptor editing helps to refine the B cell repertoire and promote selftolerance by reducing the likelihood of generating autoreactive B cells. Overall, positive selection promotes the survival of lymphocytes with weak interactions with self-antigens, while negative selection eliminates lymphocytes with strong reactivity to self-antigens. Receptor editing in B cells provides an additional mechanism to modify antigen receptor specificity and avoid autoreactivity. Together, these processes contribute to the establishment of a functional and self-tolerant immune system. You Key events in B cell maturation Two rounds Sequential rearrangement Change as maturation proceeds HCs- heavy chain and the Greek symbols are in the to the right of slide lCs- the Greek symbols to the right of slide The light chains to rearrange after the heavy chains Ig expression Surface marker change as the maturation proceeds (this is how they know what stage the cells is at) Which chain is recombines first is something that would be on the test just the basics some up with some basic question off of this chart Pre- B you are still not recongzing antigen this doesn’t happen until the b cell is mature explain in detail ChatGPT ChatGPT B cell maturation involves several key events that occur in a highly regulated manner to ensure the generation of functional B cells capable of recognizing and responding to antigens. Let's break down the key events in B cell maturation as described: 1.Two Rounds of Sequential Rearrangement: 1. B cell maturation involves two rounds of sequential rearrangement of immunoglobulin (Ig) genes, which encode the heavy and light chains of the B cell receptor (BCR). 8 2. During the first round, the genes encoding the heavy chain (HCs) undergo rearrangement, resulting in the assembly of the variable (V), diversity (D, if applicable), and joining (J) gene segments. 3. After the successful rearrangement of the heavy chain genes, the B cell proceeds to the second round of rearrangement, where the genes encoding the light chain (LCs) undergo rearrangement. 1.Change as Maturation Proceeds: 1. As B cell maturation progresses, there are changes in surface marker expression and Ig expression. 2. Surface markers, such as CD19, CD20, and CD22, may be expressed at different stages of B cell development, serving as markers to identify and characterize the maturation state of the B cell. 3. Ig expression also changes during maturation, with immature B cells expressing IgM on their surface initially and mature B cells expressing both IgM and IgD. 2.Sequence of Rearrangement: 1. One important aspect of B cell maturation is the sequential rearrangement of Ig genes, where the heavy chain genes are rearranged before the light chain genes. 2. This sequential rearrangement ensures that the B cell generates a functional BCR with both heavy and light chains that can recognize antigens. 3.Antigen Recognition: 1. In the early stages of B cell development (pre-B stage), the B cell does not recognize antigen. Antigen recognition by the BCR typically occurs after the B cell has completed maturation and exits the bone marrow. 2. Mature B cells with functional BCRs are capable of recognizing specific antigens, leading to B cell activation and the initiation of an immune response. Based on this information, some basic questions related to B cell maturation could include: What are the two rounds of sequential rearrangement involved in B cell maturation? Which genes rearrange first during B cell maturation: heavy chain genes or light chain genes? How does surface marker expression change during B cell maturation, and why is it important? At which stage of B cell development does antigen recognition by the BCR occur? What are the key differences in Ig expression between immature and mature B cells? You Actions of the Pre-B cell receptor Composed of: Two heavy chains Two ”surrogate” light chains (invariant) An Iga / Igb heterodimer Functions by ligand-independent signaling? Allelic expression ensures each B cells will only express one HC sequence 8 and thus one unquie antigen receptor First it acts to inhibit heavy chain recombination, thereby favoring a phenomenon called allelic exclusion. As a reminder, as diploid organisms, we each inherit two copies of each antigen receptor locus, one from mom and one from dad. If the heavy chain is produced from the recombined locus on one homologous chromosome and forms the pre- B cell receptor, this receptor will block rearrangement of the heavy chain locus on the other chromosome. This insures the descendent B cells will only express one heavy chain sequence and thus one unique antigen receptor. If the first rearrangement results in a nonfunctional protein chain, the heavy chain allele on the other chromosome can complete the DJ rearrangement. If neither heavy chain allele can produce functional protein than the cell will die because no survival signal will be generated. Third, functional pre-B cell receptor activates light chain recombination while simultaneously shutting off surrogate light chain transcription. This sets the stage for creation of antigen specific light chain as maturation continues Heavy chain is rearrange first and tested first Two Surrogate are the temporary light chains and they are invariant A functional Pre-BCR promotes to all the responses to the pre B. cell receptor How man y versions of an atigen does A mature receptor chain does a mature B cell express- just oen but have to loci And a immature will have 2 explain all of this in detail ChatGPT ChatGPT The pre-B cell receptor (pre-BCR) plays a critical role in the maturation of B cells, ensuring the generation of functional B cells capable of recognizing specific antigens. Let's delve into the functions and actions of the pre-BCR in detail: Composition of the Pre-BCR: The pre-BCR is composed of several components: Two heavy chains: These are rearranged during the early stages of B cell development and form the backbone of the B cell receptor. Two "surrogate" light chains: These are temporary light chains that are invariant and assist in the assembly and testing of the pre-BCR. An Igα/Igβ heterodimer: This heterodimer is associated with the heavy chains and is involved in signal transduction. Functions of the Pre-BCR: 1.Allelic Exclusion: 1. One crucial function of the pre-BCR is to promote allelic exclusion, ensuring that each mature B cell expresses only one unique antigen receptor. 2. Allelic exclusion occurs because the successful assembly and expression of the pre-BCR on one chromosome suppresses further rearrangement of the heavy chain genes on the other chromosome. 3. This ensures that only one heavy chain sequence is expressed in the mature B cell, preventing the production of B cells with multiple antigen 8 receptor specificities. 2. Activation of Light Chain Recombination: 1. The pre-BCR also plays a role in activating the rearrangement of light chain genes (κ or λ) in the B cell. 2. Once the pre-BCR is successfully assembled and expressed on the B cell surface, it triggers signaling pathways that promote the rearrangement of light chain genes. 3. This sets the stage for the creation of a complete and functional B cell receptor with both heavy and light chains. 3.Surrogate Light Chain Transition: 1. Initially, the B cell expresses surrogate light chains along with the heavy chains to form the pre-BCR. 2. The presence of surrogate light chains assists in the testing of the functionality of the heavy chain and facilitates the assembly of the preBCR. 3. As the B cell matures and progresses through development, the expression of surrogate light chains is shut off, and the B cell transitions to the expression of functional light chains. Number of Antigen Receptor Versions: A mature B cell expresses only one version of an antigen receptor. However, during the maturation process, immature B cells may initially express two versions of the antigen receptor (one from each chromosome). Allelic exclusion ensures that only one of these versions becomes functional, leading to the expression of a single unique antigen receptor on the mature B cell. In summary, the pre-BCR orchestrates several critical processes during B cell maturation, including promoting allelic exclusion, activating light chain rearrangement, and transitioning from surrogate to functional light chains. This ensures the generation of mature B cells with a single, functional antigen receptor and the ability to mount effective immune responses against specific antigens. You Key events in T cell maturation Like B cell maturation in many ways but critical differences exist Sequential rearrangement Change as maturation proceeds Thymucite is t cells in the thymus Mature T cells they will either stop producing cd4 cells and will produce cd8 or it wil stop producing cd8 and produce cd4 The different between double and and positive slection and positive and negative elimination explain all of this in detail ChatGPT ChatGPT Certainly! T cell maturation is a complex process that involves several key events, some of which are similar to B cell maturation, but with critical differences. Let's explore the key events in T cell maturation in detail: 1.Sequential Rearrangement: 8 1. Similar to B cells, T cells undergo sequential rearrangement of their antigen receptor genes during maturation in the thymus. 2. T cell receptor (TCR) genes consist of α and β chains (for αβ T cells) or γ and δ chains (for γδ T cells), and these genes undergo rearrangement in a stepwise manner to generate diverse TCR specificities. 3. The process of rearrangement involves the assembly of variable (V), diversity (D, for β and δ chains), and joining (J) gene segments to form functional TCR genes. 1.Changes as Maturation Proceeds: 1. During T cell maturation in the thymus, immature thymocytes undergo various stages of development characterized by changes in surface marker expression. 2. These changes in surface marker expression serve as indicators of the maturation state of the thymocytes and help to identify different stages of T cell development. 3. For example, double-negative (CD4-CD8-) thymocytes progress through stages characterized by the expression of different combinations of CD44, CD25, and CD117 surface markers before transitioning to double-positive (CD4+CD8+) thymocytes. 2.Positive and Negative Selection: 1. Positive selection is a critical process during T cell maturation that occurs in the thymic cortex. 2. Thymocytes that express TCRs capable of weakly interacting with selfpeptide-major histocompatibility complex (MHC) molecules presented by thymic epithelial cells receive survival signals and progress to become mature T cells. 3. Negative selection, on the other hand, occurs in the thymic medulla and involves the elimination of thymocytes that strongly react to self-peptideMHC complexes. 4. Thymocytes that recognize self-antigens too strongly undergo apoptosis to prevent the development of autoimmune responses. 3.Mature T Cell Differentiation: 1. Once thymocytes successfully undergo positive selection and negative selection, they differentiate into either CD4+ helper T cells or CD8+ cytotoxic T cells based on the presence of CD4 or CD8 co-receptors. 2. CD4+ T cells primarily help coordinate immune responses by secreting cytokines and assisting other immune cells, while CD8+ T cells primarily kill infected or abnormal cells. 4.Single-Positive T Cell Production: 1. Mature T cells express either CD4 or CD8, but not both. This decision is made during thymocyte maturation and involves the downregulation of one co-receptor and the upregulation of the other. 8 2. T cells that downregulate CD4 and upregulate CD8 become cytotoxic T cells, while those that downregulate CD8 and upregulate CD4 become helper T cells. In summary, T cell maturation involves sequential rearrangement of TCR genes, changes in surface marker expression, positive and negative selection processes, and differentiation into mature CD4+ helper T cells or CD8+ cytotoxic T cells. These processes are essential for generating a diverse repertoire of functional T cells capable of recognizing and responding to a wide range of pathogens while maintaining self-tolerance. You Actions of the Pre-T cell receptor Composed of: TCR beta chain A pre-Ta invariant chain Two CD3 dimers A zeta chain dimer Functions by ligand-independent signaling A functional Pre-TCR promotes - inhibition of beta chain gene recombination proliferate of pre-T cells - Stimulation of alpha chain recombination - expression of CD4 and CD8 - shut off of pTalpha transcription explain all this in detail ChatGPT ChatGPT The pre-T cell receptor (pre-TCR) is a crucial checkpoint in T cell development that plays a significant role in the maturation of T cells in the thymus. Let's explore the composition and functions of the pre-TCR in detail: Composition of the Pre-TCR: 1.TCR Beta Chain: The pre-TCR consists of a TCR beta chain, which is involved in antigen recognition and forms the backbone of the TCR complex. 2.Pre-Ta Invariant Chain: This chain is unique to the pre-TCR and serves as a surrogate for the TCR alpha chain. It assists in the assembly and stabilization of the pre-TCR complex. 3.CD3 Dimers: The pre-TCR complex contains two CD3 dimers (composed of CD3γε and CD3δε), which are associated with the TCR beta chain. CD3 molecules are involved in signal transduction and activation of T cells. 4.Zeta Chain Dimer: Two zeta chain dimers are also part of the pre-TCR complex. The zeta chains are essential components of the TCR signaling complex and play a role in signal transduction. Functions of the Pre-TCR: 1.Inhibition of Beta Chain Gene Recombination: 1. One of the critical functions of the pre-TCR is to inhibit further rearrangement of the TCR beta chain genes (V-D-J rearrangement). 2. This inhibition ensures that the T cell commits to the alpha-beta lineage and prevents the expression of alternative TCR chains, such as gammadelta. 3. Once a functional pre-TCR is expressed on the cell surface, signaling pathways are activated that suppress further rearrangement of TCR beta chain genes. 8 2. Proliferation of Pre-T Cells: 1. The expression of a functional pre-TCR promotes the proliferation of preT cells, leading to the expansion of the T cell population in the thymus. 2. Proliferation of pre-T cells is essential for generating a sufficient number of T cells with diverse TCR specificities. 3.Stimulation of Alpha Chain Recombination: 1. Activation of the pre-TCR signaling pathway also stimulates the rearrangement of TCR alpha chain genes (V-J rearrangement). 2. This results in the assembly of the complete TCR complex, consisting of both alpha and beta chains. 4.Expression of CD4 and CD8: 1. The pre-TCR signaling pathway promotes the expression of both CD4 and CD8 co-receptors on the surface of pre-T cells. 2. This allows pre-T cells to undergo positive selection in the thymus and differentiate into mature CD4+ helper T cells or CD8+ cytotoxic T cells. 5.Shut Off of Pre-Ta Transcription: 1. As pre-T cells progress through maturation, the expression of the pre-Ta chain is shut off. 2. This transition from pre-T cell to double-positive (CD4+CD8+) thymocytes marks the completion of the beta-selection checkpoint and the onset of positive selection. In summary, the pre-TCR plays a critical role in T cell development by promoting proliferation, inhibiting further rearrangement of TCR beta chain genes, stimulating alpha chain rearrangement, and promoting the expression of CD4 and CD8 coreceptors. These functions ensure the generation of a diverse repertoire of functional T cells capable of recognizing and responding to a wide range of antigens. You T cell development in the thymus From bone marrow See Figure 2.12 (p. 31) for a description of thymus morphology (if interested) T cells from the bone marrow and then fo to pro-t and progress in the thymus then gets deeper in the thymus and gets more specialized ChatGPT ChatGPT Certainly! T cell development in the thymus is a complex process that begins with the migration of progenitor cells from the bone marrow to the thymus. Let's outline the key stages of T cell development in the thymus: 1.Migration from Bone Marrow to Thymus: 1. Progenitor cells, originating from the bone marrow, migrate to the thymus, where they undergo further differentiation and maturation. 2.Early Stages of Thymic Development: 1. Progenitor cells entering the thymus are termed pro-T cells. 2. Within the thymus, pro-T cells progress through various stages of 8 differentiation, characterized by changes in surface marker expression. 3. These stages include the transition from double-negative (CD4-CD8-) to double-positive (CD4+CD8+) thymocytes. 1.Positive Selection: 1. Double-positive thymocytes undergo positive selection, a crucial step in T cell development. 2. Positive selection occurs in the cortex of the thymus and involves the recognition of self-peptide-major histocompatibility complex (MHC) molecules by the T cell receptor (TCR). 3. Thymocytes expressing TCRs capable of weakly interacting with self-MHC molecules receive survival signals and progress to become mature T cells. 2.Negative Selection: 1. Thymocytes that pass positive selection proceed to the medulla of the thymus, where they undergo negative selection. 2. Negative selection involves the elimination of thymocytes that strongly react to self-peptide-MHC complexes, preventing the development of autoreactive T cells. 3.Differentiation and Maturation: 1. Thymocytes that successfully undergo positive and negative selection differentiate into either CD4+ helper T cells or CD8+ cytotoxic T cells based on the expression of CD4 and CD8 co-receptors. 2. Mature T cells egress from the thymus and enter the peripheral circulation, where they play essential roles in adaptive immune responses. Overall, T cell development in the thymus involves a series of tightly regulated stages, including positive and negative selection, leading to the generation of a diverse repertoire of functional T cells capable of recognizing a wide range of antigens while maintaining self-tolerance. The morphology of the thymus, as described in Figure 2.12, reflects its unique structure, with distinct cortical and medullary regions where different stages of T cell development occur. You Inward” migration depends on chemokines/ migration ensures sequential exposure to signals and interactions Cell when migration is inwards will continue maturation and will interact with different cells Positive selection- weak recognition of self Double positive cells is no cells reconigtion Negative slection- this is when they become cd4 or cd8 cells and this selection is strong recognition of self (2nd round) Cd4 + treg suruive slection under (look at powerpoint didn’t get full notes) Estimated that 95% of t cells DIE DURING MATURATION ChatGPT ChatGPT The inward migration of T cells in the thymus is a highly orchestrated process driven by chemokines and ensures that T cells are sequentially exposed to various signals 8 and interactions crucial for their maturation. Here's a breakdown of the key points regarding T cell migration and selection in the thymus: 1. Chemokine-Driven Migration: 1. Chemokines are signaling molecules that guide the migration of cells, including T cells, within tissues. 2. In the thymus, chemokines play a vital role in directing the inward migration of T cell precursors from the corticomedullary junction towards the thymic cortex, where T cell maturation primarily occurs. 3. This inward migration ensures that T cells encounter specific microenvironments within the thymus, where they receive signals necessary for their development. 2.Sequential Exposure to Signals and Interactions: 1. As T cells migrate inward through the thymus, they encounter various stromal cells, antigen-presenting cells (APCs), and other thymocytes. 2. Each microenvironment provides distinct signals and interactions that influence T cell development and maturation. 3. Sequential exposure to these signals and interactions is critical for guiding T cells through different stages of development, including positive and negative selection. 3.Positive Selection: 1. Positive selection occurs in the cortex of the thymus and involves the recognition of self-peptide-MHC complexes by the T cell receptor (TCR). 2. Thymocytes expressing TCRs capable of weakly interacting with self-MHC molecules receive survival signals and proceed with maturation. 3. This process ensures that T cells have the ability to recognize self-MHC molecules, a crucial requirement for their function in the periphery. 4.Negative Selection: 1. Negative selection occurs in the thymic medulla and involves the elimination of thymocytes that strongly react to self-peptide-MHC complexes. 2. Thymocytes that fail negative selection are eliminated through apoptosis to prevent the development of autoreactive T cells. 3. This process is critical for establishing central tolerance and preventing autoimmunity. 5.T Cell Survival and Apoptosis: 1. It is estimated that the majority of thymocytes, approximately 95%, undergo apoptosis during T cell maturation in the thymus. 2. Only a small fraction of thymocytes that successfully undergo positive and negative selection survive to become mature T cells and exit the thymus. In summary, inward migration of T cells in the thymus, guided by chemokines, ensures sequential exposure to signals and interactions critical for T cell 8 development. Positive selection promotes the survival of T cells capable of recognizing self-MHC molecules, while negative selection eliminates thymocytes with strong reactivity to self-antigens. The rigorous selection processes in the thymus are essential for generating a diverse repertoire of functional T cells while maintaining self-tolerance. You T cell activation Days after infection and the effector cells are produced because of immune resonse and they will expand in number and this is clonal expanision after infection the cells will experenice contraction and then the cd8 and cd4 cells some will remain has memory cells - clonal expansion - contraction (homostasis) -memory ChatGPT ChatGPT T cell activation is a critical process in the adaptive immune response that occurs following the recognition of antigens presented by antigen-presenting cells (APCs). Here's an overview of the key stages of T cell activation and the subsequent generation of effector and memory T cells: 1.Recognition of Antigen: 1. T cell activation begins when a T cell receptor (TCR) on the surface of a T cell binds to a specific antigen peptide presented by major histocompatibility complex (MHC) molecules on the surface of APCs. 2. This interaction is facilitated by co-stimulatory molecules such as CD28 on the surface of T cells and CD80/CD86 on the surface of APCs. 2.Clonal Expansion: 1. Upon antigen recognition and co-stimulation, the activated T cell undergoes clonal expansion. 2. Clonal expansion involves the rapid proliferation of the activated T cell, leading to the generation of a large number of effector T cells with identical antigen specificity. 3. This expansion phase allows the immune system to mount a robust and specific response against the invading pathogen. 3.Effector Cell Differentiation: 1. During clonal expansion, activated T cells differentiate into effector T cells with specialized functions. 2. CD4+ T cells differentiate into various subsets such as T helper 1 (Th1), Th2, Th17, or regulatory T (Treg) cells, depending on the cytokine milieu and signals received during activation. 3. CD8+ T cells differentiate into cytotoxic T lymphocytes (CTLs) capable of directly killing infected or abnormal cells. 4.Contraction (Homostasis): 1. Following the peak of the immune response, the number of effector T cells declines through a process known as contraction or homostasis. 2. During contraction, the majority of effector T cells undergo apoptosis, 8 reducing their numbers to pre-infection levels. 3. This phase helps to prevent excessive immune activation and tissue damage. 1.Memory T Cell Generation: 1. A subset of activated T cells survives the contraction phase and differentiates into long-lived memory T cells. 2. Memory T cells possess enhanced responsiveness to antigen re-exposure and provide immunological memory. 3. Memory T cells can rapidly proliferate and differentiate into effector T cells upon encountering the same antigen during a secondary infection, leading to a faster and more robust immune response. In summary, T cell activation involves a series of coordinated events, including clonal expansion, effector cell differentiation, contraction, and memory T cell generation. These processes are crucial for mounting an effective immune response against pathogens and providing long-term immunity to prevent reinfection. You T cell life history events HSCs--> Naïve T cells---> Activated T cells--->Effector T cells & Memory T cells-->Memory T cells Start with hscs (maturation) - naïve T cells (recognition of antigen)-- activated T cells ( proliferation and differentiation) -effector T cells and memory cells ( elimination of antigen contraction (death of effector cells)-- memory cells explain in detail ChatGPT ChatGPT Certainly! The life history of T cells encompasses various stages, from their development from hematopoietic stem cells (HSCs) to their role in the adaptive immune response as effector and memory cells. Let's delve into each stage in detail: 1.Hematopoietic Stem Cells (HSCs): 1. T cell development begins in the bone marrow, where hematopoietic stem cells (HSCs) differentiate into progenitor cells committed to the lymphoid lineage. 2. These progenitor cells migrate to the thymus, where they undergo further maturation into naïve T cells. 2.Naïve T Cells: 1. Naïve T cells are mature T cells that have not yet encountered their cognate antigen. 2. These T cells express a diverse repertoire of T cell receptors (TCRs) capable of recognizing specific antigens presented by major histocompatibility complex (MHC) molecules. 3. Naïve T cells circulate through the blood and lymphoid tissues, constantly surveying for antigens. 3.Activation of T Cells: 1. Upon encountering their cognate antigen presented by antigen- 8 presenting cells (APCs), such as dendritic cells, naïve T cells become activated. 2. T cell activation involves the binding of the TCR to the antigen-MHC complex and co-stimulatory signals provided by molecules such as CD28 and CD80/86. 3. Activated T cells undergo proliferation and differentiation into effector T cells, which mediate various functions in the immune response. 1.Effector T Cells and Memory T Cells: 1. Effector T cells are the immediate responders to antigen encounter and are specialized for specific functions. 2. CD4+ effector T cells can differentiate into subsets such as T helper 1 (Th1), Th2, Th17, or regulatory T (Treg) cells, depending on the cytokine milieu. 3. CD8+ effector T cells, also known as cytotoxic T lymphocytes (CTLs), directly kill infected or abnormal cells. 4. Memory T cells are a long-lived subset of T cells that arise during the primary immune response and persist after antigen clearance. 5. Memory T cells exhibit rapid recall responses upon re-encountering the same antigen, leading to a faster and more robust secondary immune response. 2.Contraction and Maintenance of Memory: 1. After the peak of the immune response, the population of effector T cells declines through a process called contraction. 2. The majority of effector T cells undergo apoptosis, while a small fraction survives and differentiates into long-lived memory T cells. 3. Memory T cells persist in the body for an extended period, providing immunological memory and protection against reinfection. In summary, the life history of T cells involves a series of stages, from development in the bone marrow to activation, differentiation into effector cells, contraction, and generation of memory cells. These processes are essential for mounting effective immune responses against pathogens and providing long-term immunity. You Activation of naïve and effector T cells by antigen Lymphocytes respond to antigen at two points in their life history We are looking at lymmnode and this is were the t ells hang out.. The dentritic cells will interact with t cells and find antigen What do APCS DO They display antigens - provide singnas that guide T cells response costimulators and Cyotkines explain in de3tail ChatGPT ChatGPT Antigen-presenting cells (APCs) play a crucial role in initiating and regulating immune responses by presenting antigens to T cells. Here's a detailed explanation of what APCs do and how they activate naïve and effector T cells: 8 1. Antigen Presentation: 1. APCs capture antigens from pathogens, such as bacteria or viruses, through processes such as phagocytosis or endocytosis. 2. Once inside the APC, antigens are processed into peptide fragments. 3. These peptide fragments are then loaded onto major histocompatibility complex (MHC) molecules, which serve as molecular platforms for presenting antigens to T cells. 4. APCs can express both MHC class I molecules (presenting endogenous antigens to CD8+ T cells) and MHC class II molecules (presenting exogenous antigens to CD4+ T cells). 2.Signal Provision: 1. In addition to antigen presentation, APCs provide signals that guide T cell responses. 2. Co-stimulatory molecules, such as CD80 (B7.1) and CD86 (B7.2), on the surface of APCs interact with CD28 receptors on T cells to provide a crucial second signal for T cell activation. 3. Without co-stimulation, T cell activation may be aborted, leading to tolerance rather than an immune response. 4. Cytokines secreted by APCs also influence T cell activation and differentiation. For example, dendritic cells can produce interleukin-12 (IL-12), which promotes the differentiation of naïve CD4+ T cells into Th1 cells. 3.Activation of Naïve T Cells: 1. Naïve T cells continuously circulate through secondary lymphoid organs such as lymph nodes, where they survey APCs for antigen presentation. 2. When a naïve T cell encounters an APC presenting its cognate antigen peptide-MHC complex along with co-stimulatory signals, it becomes activated. 3. This activation leads to clonal expansion and differentiation of the naïve T cell into effector T cells, which mediate immune responses against the antigen. 4.Activation of Effector T Cells: 1. Effector T cells, which are already primed and circulating in the bloodstream or lymphoid tissues, can also be activated by APCs presenting antigens. 2. This activation occurs when effector T cells encounter APCs presenting antigens that match their TCR specificity. 3. The interaction between the TCR on the effector T cell and the peptideMHC complex on the APC, along with co-stimulatory signals, reinforces T cell activation and promotes effector functions such as cytokine production or cytotoxicity. In summary, APCs play a central role in immune responses by capturing, processing, 8 and presenting antigens to T cells. Through antigen presentation and provision of costimulatory signals and cytokines, APCs activate both naïve and effector T cells, initiating and regulating adaptive immune responses against pathogens and foreign antigens. You Sequence of events in T cell responses Numerous cytokines drive the progression APCs Express both MHC II & MHC I Display antigen Provide signals that guide T cell response => Costimulators & Cytokines They are not actually identifical effector functions - activation of macrophages, B cells, other cells, inflammation killing of infected cells macrophages activation - then things dealing with the lymphoid organ ChatGPT ChatGPT The sequence of events in T cell responses involves a series of coordinated interactions between antigen-presenting cells (APCs), T cells, and other immune cells. Here's a detailed explanation of the key steps in the T cell response: 1.Antigen Presentation by APCs: 1. Antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B cells, capture antigens from pathogens or infected cells. 2. APCs process these antigens into peptide fragments and present them on their cell surface using major histocompatibility complex (MHC) molecules. 3. APCs express both MHC class I molecules (presenting endogenous antigens to CD8+ T cells) and MHC class II molecules (presenting exogenous antigens to CD4+ T cells). 2.Activation of Naïve T Cells: 1. Naïve T cells continuously circulate through secondary lymphoid organs, such as lymph nodes, where they encounter APCs presenting antigens. 2. When a naïve T cell recognizes its cognate antigen presented by an APC, along with co-stimulatory signals provided by molecules such as CD80/CD86, it becomes activated. 3. This activation leads to the clonal expansion and differentiation of naïve T cells into effector T cells with specialized functions. 3.Effector Functions of T Cells: 1. Activated effector T cells migrate to sites of infection or inflammation, where they exert their effector functions. 2. CD4+ T helper (Th) cells release cytokines to activate and recruit other immune cells, such as macrophages, B cells, and cytotoxic T cells, to eliminate pathogens. 3. Th1 cells produce interferon-gamma (IFN-gamma) to activate macrophages, enhancing their ability to kill intracellular pathogens. 4. Th2 cells secrete cytokines such as interleukin-4 (IL-4) and interleukin-5 (IL-5) to promote antibody production by B cells and the elimination of 8 extracellular parasites. 5. Cytotoxic CD8+ T cells directly kill infected or abnormal cells by releasing cytotoxic molecules such as perforin and granzymes. 1.Resolution of Infection and Tissue Repair: 1. As the immune response progresses, effector T cells, along with other immune cells, work together to eliminate the pathogen and resolve the infection. 2. Regulatory T cells (Tregs) help to dampen excessive immune responses and prevent tissue damage caused by inflammation. 3. Once the infection is cleared, the majority of effector T cells undergo apoptosis, while a small fraction differentiates into long-lived memory T cells. 2.Memory T Cell Formation: 1. Memory T cells persist in the body after the resolution of infection and provide immunological memory. 2. Memory T cells are poised to rapidly respond to re-infection with the same pathogen, leading to a faster and more robust secondary immune response. In summary, the sequence of events in T cell responses involves antigen presentation by APCs, activation of naïve T cells, effector functions mediated by activated T cells, resolution of infection, and the formation of memory T cells. These processes are essential for effective immune responses against pathogens and the maintenance of long-term immunity. You Cytokines typically “tell” the responding cell to ______________. alter expression of certain genes begin chemotaxis undergo apoptosis suppress metabolic activity ChatGPT ChatGPT Cytokines typically "tell" the responding cell to alter the expression of certain genes. Cytokines are signaling molecules produced by various immune cells, including T cells, B cells, macrophages, and dendritic cells, among others. When released, cytokines bind to specific receptors on the surface of target cells, triggering intracellular signaling pathways that lead to changes in gene expression. These changes can influence a wide range of cellular processes, including proliferation, differentiation, migration, and activation. Therefore, cytokines play critical roles in modulating immune responses, inflammation, and various physiological processes by regulating gene expression in target cells. You Costimulators are important for T cell activation A- THE APC has not be activated yet the apc has cd28 which is a cell surface antigen ( the t cell resposnr is no response or tolerance) – for example to self antigen This shows that cosimitulators are Important B- APC activated by microbes innate immune responses( cytokines) increased 8 expression of costimulators. Then gene expression for IL-2 and the effector t cells ( T cell survival, proliferation and differentiation) Ctokines are good at producing IL-2 cells explain in detail ChatGPT ChatGPT Certainly! Costimulatory signals are indeed crucial for T cell activation, and they play essential roles in regulating immune responses. Let's explore each scenario in detail: Scenario A: In the absence of costimulatory signals, T cell activation may not occur, or the T cell may become tolerant to the antigen. For instance, if an antigen-presenting cell (APC) presents a self-antigen to a T cell without providing costimulatory signals, the T cell may not respond or may even become tolerant to the self-antigen. One of the key costimulatory molecules involved in T cell activation is CD28, which is expressed on the surface of T cells. CD28 interacts with CD80 (B7.1) and CD86 (B7.2) molecules on the surface of APCs to provide a crucial second signal for T cell activation. Therefore, the presence or absence of costimulatory signals, such as CD28-B7 interactions, can determine whether a T cell becomes activated or tolerant to the antigen presented by the APC. Scenario B: When an APC encounters microbial pathogens or activates innate immune responses, it increases the expression of costimulatory molecules, such as CD80 and CD86. This upregulation of costimulatory molecules enhances the ability of the APC to provide costimulatory signals to T cells during antigen presentation. Additionally, innate immune responses triggered by microbial pathogens can lead to the production of proinflammatory cytokines, such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). These cytokines further stimulate the expression of costimulatory molecules on APCs and promote T cell activation and differentiation. Upon activation by APCs presenting antigens and providing costimulatory signals, T cells upregulate the expression of interleukin-2 (IL-2) and its receptor (IL-2R). IL-2 plays a critical role in T cell survival, proliferation, and differentiation into effector T cells. It promotes the expansion of activated T cells and supports their effector functions. Scenario C: Cytokines secreted by various immune cells, including T cells, APCs, and other leukocytes, play important roles in modulating immune responses. Among these cytokines, interleukin-2 (IL-2) is particularly important for T cell activation and proliferation. IL-2 is produced primarily by activated T cells themselves, particularly CD4+ helper T cells. It acts in an autocrine and paracrine manner to stimulate the proliferation and 8 differentiation of T cells. IL-2 signaling through its receptor (IL-2R) promotes T cell survival, expansion, and differentiation into effector T cells, which mediate immune responses against pathogens. In summary, costimulatory signals provided by APCs, along with proinflammatory cytokines and IL-2 produced during immune responses, are critical for T cell activation, proliferation, and differentiation into effector T cells. These signals orchestrate the adaptive immune response and help regulate the magnitude and duration of immune responses against pathogens. You Costimulators in APC-T cell interactions Expressed in response to microbial products and various cytokines B7 anti-presenting cells binding to t receptors and then expression happens which is cd28 (regularory t cells and activated t cells) 87/CD28 more important for activation of. Aive T cells than for the stimulation of effector or memory cells Ctla-4- naïve t cells and inhibition of t cell activation PD-1- activated t cells ( inhibiation of T cell activation (mainly of effector t cells) Some costimulators are inhibitory CTLA-4 acts as competivotve inhibitor of CD28 PD-1 sends inhibitor signals upon binding to its ligand explain all of this in detail ChatGPT ChatGPT Certainly! Costimulatory molecules play crucial roles in regulating T cell activation and function during immune responses. Let's delve into the details of the key costimulators and their functions: 1.B7/CD28 Pathway: 1. B7 molecules (CD80 and CD86) are expressed on the surface of antigenpresenting cells (APCs) in response to microbial products and various cytokines. 2. When APCs present antigens to T cells, they also express B7 molecules, which interact with the CD28 receptor on T cells. 3. CD28-B7 interactions provide essential costimulatory signals that enhance T cell activation, proliferation, and differentiation into effector T cells. 4. CD28 engagement promotes the production of interleukin-2 (IL-2) and the expression of other cytokines necessary for T cell activation and function. 5. Regulatory T cells (Tregs) also express CD28, which is involved in their activation and suppressive functions. 2.CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4): 1. CTLA-4 is structurally similar to CD28 and competes with CD28 for binding to B7 molecules on APCs. 2. Unlike CD28, which promotes T cell activation, CTLA-4 acts as a negative regulator of T cell activation. 8 3. CTLA-4 is upregulated on activated T cells, including naïve T cells, and functions to dampen immune responses. 4. When CTLA-4 engages with B7 molecules, it sends inhibitory signals that suppress T cell activation and proliferation. 5. The inhibitory function of CTLA-4 helps prevent excessive or prolonged immune responses and maintains immune homeostasis. 1.PD-1 (Programmed Cell Death Protein 1): 1. PD-1 is another inhibitory receptor expressed on activated T cells, primarily effector T cells, upon antigen encounter. 2. PD-1 interacts with its ligands, PD-L1 (programmed death-ligand 1) and PD-L2, which are expressed on the surface of APCs and other cells. 3. Binding of PD-1 to its ligands delivers inhibitory signals that dampen T cell activation and effector functions. 4. PD-1 signaling is crucial for regulating immune responses and preventing excessive tissue damage and autoimmunity. 5. However, PD-1 can also be exploited by pathogens and tumors to evade immune surveillance by suppressing T cell responses. In summary, costimulatory molecules such as CD28 provide essential signals for T cell activation and effector functions, while inhibitory receptors like CTLA-4 and PD-1 serve as checkpoints to regulate immune responses and maintain immune tolerance. The balance between costimulatory and inhibitory signals is critical for modulating the magnitude and duration of immune responses and preventing immune-related disorders. 1/2 You Manipulation of the B7/CD28 interaction for therapeutic purposes normal signalingactivation recombinant "drug" - costimulatory blockade - CTLA-4 APPROVED for RA and tissue transplant explain in detail ChatGPT ChatGPT Manipulation of the B7/CD28 interaction for therapeutic purposes involves targeting the costimulatory pathway to modulate immune responses. This manipulation can have significant implications for treating various immune-related disorders. Let's explore this in detail: 1.Normal Signaling - Activation: 1. In normal immune responses, the interaction between the B7 molecules (CD80 and CD86) on antigen-presenting cells (APCs) and the CD28 receptor on T cells provides essential costimulatory signals for T cell activation. 2. Upon antigen recognition and engagement of the T cell receptor (TCR) with the peptide-MHC complex on APCs, CD28 engagement by B7 molecules enhances T cell activation, proliferation, and differentiation 8 into effector T cells. 3. This normal signaling cascade is crucial for mounting effective immune responses against pathogens and maintaining immune surveillance. 1.Recombinant "Drug" - Costimulatory Blockade: 1. Costimulatory blockade involves interfering with the B7/CD28 interaction to modulate T cell responses. 2. One approach to costimulatory blockade is the use of recombinant proteins or antibodies that target either the B7 molecules or the CD28 receptor, thereby inhibiting their interaction. 3. For example, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) acts as a competitive inhibitor of CD28 by binding to B7 molecules with higher affinity. Therefore, blocking CTLA-4 can enhance T cell activation by preventing the inhibitory signaling mediated by CTLA-4. 4. Another approach is the use of soluble forms of CTLA-4 or anti-CTLA-4 monoclonal antibodies to block CTLA-4-B7 interactions, thereby promoting T cell activation and effector functions. 5. Similarly, blocking the interaction between PD-1 and its ligands (PD-L1 and PD-L2) using monoclonal antibodies can also enhance T cell activation and antitumor immune responses by relieving the inhibitory signals mediated by PD-1. 2.Clinical Applications - CTLA-4 Approved for RA and Tissue Transplant: 1. One of the most significant clinical applications of costimulatory blockade is the use of CTLA-4 blockade for the treatment of immune-related disorders, such as rheumatoid arthritis (RA) and tissue transplantation. 2. In RA, aberrant T cell activation and inflammation contribute to joint destruction and disease progression. By blocking CTLA-4, which negatively regulates T cell activation, the immune response can be modulated, leading to reduced inflammation and joint damage. 3. In tissue transplantation, alloreactive T cells recognize and attack the transplanted tissue, leading to rejection. By blocking CTLA-4 or other costimulatory pathways, alloreactive T cell responses can be suppressed, allowing for better graft survival and reduced rejection rates. In summary, manipulation of the B7/CD28 interaction through costimulatory blockade offers promising therapeutic strategies for treating immune-related disorders, including autoimmune diseases, transplantation, and cancer. By modulating T cell activation and immune responses, these approaches aim to restore immune homeostasis and improve patient outcomes. The approval of CTLA-4 blockade for clinical use underscores the importance of targeting costimulatory pathways for therapeutic intervention in immune-mediated diseases. 8