Lecture 11 - Immunology Study Guide PDF

Hypervariable CDR loops TCR structure for CD4+ and CD8+ cells Antigen-binding region Heterodimer: a chain and b chain => “a / b T cells” Each chain composed of: Variable antigen-binding region Constant region TM domain Member of Ig superfamily Sure, let's break down the structure of T cell receptors...

Hypervariable CDR loops TCR structure for CD4+ and CD8+ cells Antigen-binding region Heterodimer: a chain and b chain => “a / b T cells” Each chain composed of: Variable antigen-binding region Constant region TM domain Member of Ig superfamily Sure, let's break down the structure of T cell receptors (TCRs) for CD4+ and CD8+ cells in detail: 1.Heterodimer Structure: 1. TCRs on both CD4+ and CD8+ cells are composed of two different protein chains, referred to as the alpha (α) chain and beta (β) chain. 2. This arrangement gives rise to what is often called "α/β T cells". 2.Composition of Each Chain: 1. Each chain (α and β) comprises several key components: 1. Variable Antigen-Binding Region: This is the part of the TCR that directly interacts with antigenic peptides presented by major histocompatibility complex (MHC) molecules on antigenpresenting cells. 2. Constant Region: This region plays a role in signaling and stabilizing the TCR complex. 3. Transmembrane (TM) Domain: This anchors the TCR in the cell membrane. 3.Member of the Immunoglobulin (Ig) Superfamily: 1. TCRs belong to the immunoglobulin superfamily due to structural similarities with antibodies. 1 2. The Ig superfamily is a large group of proteins involved in immune recognition and signaling. 1.Hypervariable Complementarity-Determining Region (CDR) Loops: 1. These loops are part of the variable antigen-binding region. 2. The CDR loops are highly variable in sequence and are responsible for directly contacting the antigen. 3. They are termed CDR1, CDR2, and CDR3, with CDR3 being the most variable and critical for antigen recognition. 2.Disulfide Bonds: 1. Disulfide bonds are covalent bonds formed between two cysteine residues. 2. They contribute to the stability and proper folding of the TCR chains. 3.Immunoglobulin (Ig) Domain: 1. This domain is characteristic of proteins in the immunoglobulin superfamily. 2. It is involved in protein-protein interactions and antigen recognition. 4.Carbohydrate Region: 1. TCRs, like many cell surface proteins, may have carbohydrate moieties attached. 2. These carbohydrates can modulate TCR function and stability. In summary, TCRs on CD4+ and CD8+ T cells are heterodimeric receptors composed of alpha and beta chains. They contain variable antigen-binding regions with hypervariable CDR loops, disulfide bonds for stability, Ig domains, and carbohydrate regions. These structures enable T cells to recognize a wide range of antigens and initiate immune responses. 1 The TCR is part of a signal transduction complex The TCR complex: Forms via noncovalent interactions Acts to transduce signal - MHC/antigen binding à T cell activation - Complex consists of: -* TCR TWO cd3 HETERODIMERS (Y/e AND LOOK AT HIS COMPLETED NOTES) One zeta homodimer Certainly, let's delve into the signal transduction complex involving the T cell receptor (TCR). Here's a detailed explanation: 1.TCR Complex Formation: 1. The TCR complex is formed through noncovalent interactions among its various components. 2. Its primary function is to transduce signals upon binding of the TCR to the major histocompatibility complex (MHC) presenting an antigen peptide. 2.Composition of the TCR Complex: 1. The TCR complex consists of several key components: 1. TCR: The T cell receptor itself, composed of α and β chains. 2. Two CD3 heterodimers: CD3εγ and CD3εδ. 3. One zeta homodimer: ζζ. 2. This complex serves as a sensor for the T cell, transducing signals upon antigen recognition. 3.Signal Transduction Mechanism: 1. When the TCR binds to the appropriate MHC/peptide partner, signaling is initiated. 2. The CD3 and ζ chains of the TCR complex contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic tails. 2 3. 4. Upon TCR engagement, ITAMs are phosphorylated by protein kinases. Phosphorylation of ITAMs serves as a signal transduction event, initiating a cascade of intracellular signaling pathways. 1.Phosphorylation Process: 1. Phosphorylation occurs on tyrosine residues within the ITAM motifs. 2. This phosphorylation event is catalyzed by protein kinases, typically associated with the TCR signaling pathway. 3. The phosphorylated ITAMs act as docking sites for other signaling molecules, recruiting them to the TCR complex to propagate the signal. 2.Localization of Phosphorylation: 1. Phosphorylation of ITAMs occurs in the cytoplasmic domain of the CD3 and ζ chains. 2. This phosphorylation event happens in the cytoplasm, following TCR engagement at the plasma membrane. 3.Functional Role of ITAMs: 1. Phosphorylated ITAMs serve as platforms for the recruitment and activation of downstream signaling molecules. 2. They are essential for the initiation and propagation of signaling events that lead to T cell activation, proliferation, and effector functions. In summary, the TCR complex, composed of the TCR itself along with CD3 and ζ chains, acts as a sensor for T cells. Upon antigen recognition, ITAMs within the CD3 and ζ chains are phosphorylated, initiating signal transduction cascades that ultimately lead to T cell activation and immune responses. 2 Ligand-receptor interactions leading to T cell activation Certainly! Let's break down the ligand-receptor interactions leading to T cell activation, specifically focusing on the role of MHC molecules, T cell receptors (TCRs), and co-receptors such as CD4 and CD8: 1.MHC-Peptide Complex Recognition: 1. Major histocompatibility complex (MHC) molecules are cell surface proteins that present antigenic peptides to T cells. 2. Class II MHC molecules typically present peptides derived from exogenous antigens to CD4+ T cells, while class I MHC molecules present peptides from endogenous antigens to CD8+ T cells. 2.TCR Binding to MHC-Peptide Complex: 1. T cell receptors (TCRs) are transmembrane proteins expressed on the surface of T cells. 2. TCRs specifically recognize and bind to the complex formed by MHC molecules presenting antigenic peptides. 3. This interaction between the TCR and the MHC-peptide complex initiates the signaling cascade leading to T cell activation. 3.Co-receptors in T Cell Activation: 1. Co-receptors are additional cell surface proteins expressed on T cells that assist in the recognition of MHC molecules and enhance T cell activation. 3 2. 3. CD4 and CD8 are two important co-receptors expressed on T cells. CD4 serves as a co-receptor for CD4+ helper T lymphocytes, while CD8 serves as a co-receptor for CD8+ cytotoxic T lymphocytes. 4. The co-receptors bind to regions of the MHC molecules distinct from those bound by the TCRs, enhancing the stability of the TCR-MHC-peptide interaction and facilitating T cell activation. 1.Role of CD4 as a Co-receptor: 1. CD4 is primarily expressed on helper T cells (CD4+ T cells). 2. When a CD4+ T cell encounters an antigen-presenting cell (APC) displaying a peptide bound to class II MHC molecules, the CD4 coreceptor binds to a region of the MHC molecule outside the peptidebinding groove. 3. This interaction stabilizes the binding of the TCR to the MHC-peptide complex and enhances T cell activation by facilitating signal transduction. 2.Role of CD8 as a Co-receptor: 1. CD8 is primarily expressed on cytotoxic T cells (CD8+ T cells). 2. Similarly, when a CD8+ T cell recognizes a peptide presented by class I MHC molecules on target cells, the CD8 co-receptor binds to the MHC molecule, enhancing the interaction between the TCR and the MHCpeptide complex. 3. This interaction plays a crucial role in activating cytotoxic T cells and facilitating their effector functions, such as killing infected or abnormal cells. In summary, ligand-receptor interactions leading to T cell activation involve the recognition of antigenic peptides presented by MHC molecules by TCRs on T cells. Coreceptors such as CD4 and CD8 enhance these interactions, stabilizing TCR-MHCpeptide binding and facilitating T cell activation and effector functions. 3 CD4 and CD8 co-receptors Key defining feature of T cell type CD4+ helper T cells (Th) CD8+ cytotoxic T cells (Tc or CTLs) CD4+ regulatory T cells (Treg) Certainly, let's delve into the details of CD4 and CD8 co-receptors, their association with specific T cell types, and their role as key defining features of T cell subsets: 1.CD4 and CD8 Co-receptors: 1. CD4 and CD8 are transmembrane glycoproteins expressed on the surface of T cells. 2. They act as co-receptors alongside the T cell receptor (TCR) to facilitate the recognition of antigens presented by major histocompatibility complex (MHC) molecules. 3. These co-receptors enhance T cell activation by stabilizing the interaction between the TCR and the MHC-peptide complex. 2.Key Defining Features of T Cell Types: 1. CD4+ Helper T cells (Th): Helper T cells express CD4 as their co-receptor. They play a central role in orchestrating immune responses by secreting cytokines that regulate the activity of other immune cells. 2. CD8+ Cytotoxic T cells (Tc or CTLs): Cytotoxic T cells express CD8 as their co-receptor. They are specialized in killing infected or abnormal cells, such as virus-infected cells or cancer cells. 3. CD4+ Regulatory T cells (Treg): Regulatory T cells also express CD4. They play a critical role in maintaining immune homeostasis by suppressing 4 excessive immune responses and preventing autoimmunity. 4. Each T cell subset has specific functions and cytokine profiles determined by the expression of particular transcription factors and surface markers. 1.Association with MHC Proteins: 1. While CD4 and CD8 co-receptors do not directly bind to MHC molecules, they interact with regions of MHC molecules outside the peptide-binding groove. 2. CD4 binds to the non-polymorphic region of class II MHC molecules, while CD8 binds to the non-polymorphic region of class I MHC molecules. 3. These interactions stabilize the binding of the TCR to the MHC-peptide complex and enhance T cell activation. 2.HIV and CD4: 1. HIV (Human Immunodeficiency Virus) uses CD4 as its primary receptor for infection. 2. The virus binds to CD4 on the surface of CD4+ T cells, leading to viral entry and subsequent infection of the host cell. 3. This interaction between HIV and CD4 ultimately leads to the depletion of CD4+ T cells, compromising the immune system's ability to mount effective responses against pathogens. In summary, CD4 and CD8 co-receptors are key defining features of specific T cell subsets, including helper T cells, cytotoxic T cells, and regulatory T cells. They facilitate T cell activation by stabilizing interactions with MHC-peptide complexes and play critical roles in immune responses and regulation. Additionally, CD4 serves as the primary receptor for HIV infection, highlighting its importance in both normal immune function and viral pathogenesis. 4 Lck phosphorylates ITAMs upon Class II MHC / peptide detection Kinase Lck is associated with cytosolic domain of CD4 Lck = lymphocyte-specific protein tyrosine kinase Let's break down the process of Lck phosphorylation of ITAMs upon Class II MHC/peptide detection in CD4+ T cells and the involvement of Lck in T cell activation: 1.Lck Phosphorylation of ITAMs: 1. Lck (Lymphocyte-specific protein tyrosine kinase) is a Src family kinase that plays a crucial role in T cell signaling. 2. Upon binding of the T cell receptor (TCR) to the complex formed by Class II MHC molecules presenting antigenic peptides, Lck becomes activated. 3. Activated Lck phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) present in the cytoplasmic tails of CD3 and ζ chains associated with the TCR complex. 4. Phosphorylation of ITAMs serves as a critical signaling event that initiates downstream signaling cascades leading to T cell activation. 2.Association of Lck with CD4: 1. Lck is associated with the cytoplasmic domain of CD4, the co-receptor expressed on CD4+ T cells. 2. Upon binding of both the TCR and CD4 to the complex formed by Class II MHC molecules presenting antigenic peptides, Lck is recruited to the TCR signaling complex. 3. The association of Lck with the cytoplasmic domain of CD4 facilitates its 5 activation and subsequent phosphorylation of ITAMs upon TCR engagement. 3. Function in CD4+ T Cells: 1. In CD4+ T cells, Lck-mediated phosphorylation of ITAMs upon Class II MHC/peptide detection is crucial for initiating signaling events leading to T cell activation. 2. This activation cascade involves the recruitment and activation of various downstream signaling molecules, leading to gene transcription, cytokine secretion, and ultimately, T cell proliferation and differentiation. 4.Similar Functions in CD8+ CTLs: 1. While Lck is primarily associated with CD4+ T cells, similar functions are performed by other Src family kinases in CD8+ cytotoxic T cells (CTLs). 2. In CD8+ CTLs, the TCR interacts with Class I MHC molecules presenting antigenic peptides, leading to the activation of Src family kinases such as Lck or Fyn. 3. These kinases phosphorylate ITAMs associated with the TCR complex, initiating signaling pathways that culminate in CTL activation and effector functions, including target cell killing. In summary, Lck plays a critical role in T cell activation by phosphorylating ITAMs upon TCR engagement with Class II MHC/peptide complexes in CD4+ T cells. Its association with the cytoplasmic domain of CD4 facilitates its recruitment to the TCR signaling complex, where it initiates downstream signaling events leading to T cell activation. Similar functions are performed by other Src family kinases in CD8+ CTLs upon engagement of the TCR with Class I MHC/peptide complexes. 5 The binding of TCR/co-receptor to MHC/antigen initiates formation of an increasingly stable “Immune Synapse” TCR-associated protein APC LFA-1-associated protein Pms nearly touching T cell View rotated 90◦ Overlay LFA-1 = leukocyte function-associated antigen 1 (integrin) Certainly! Let's explore the process of leukocytes exiting the bloodstream by interacting with integrins and forming an immune synapse with antigen-presenting cells (APCs) in detail: 1.Leukocyte Extravasation: 1. Leukocytes, such as T cells, must exit the bloodstream to reach sites of infection or inflammation in tissues. 2. This process, called extravasation or diapedesis, involves leukocytes adhering to and migrating through the endothelial cells lining blood vessels. 2.Role of Integrins: 1. Integrins are cell adhesion molecules expressed on the surface of leukocytes. 2. One important integrin involved in leukocyte extravasation is leukocyte function-associated antigen 1 (LFA-1). 3. LFA-1 binds to its ligands, such as intercellular adhesion molecules (ICAMs), which are expressed on the surface of endothelial cells during inflammation. 3.Formation of Immune Synapse: 1. When T cells encounter antigen-presenting cells (APCs) presenting their 6 cognate antigen on MHC molecules, the TCR/co-receptor complex binds to the MHC/antigen complex on the APC. 2. This interaction triggers the formation of an immune synapse, a specialized junction between the T cell and the APC. 3. The immune synapse is characterized by a central cluster of TCRs and associated signaling molecules surrounded by a ring of adhesion molecules, including LFA-1. 1.Leukocyte Adhesion to Endothelial Cells: 1. In the bloodstream, leukocytes interact with endothelial cells expressing adhesion molecules such as ICAM-1. 2. Engagement of LFA-1 on leukocytes with ICAM-1 on endothelial cells leads to firm adhesion of leukocytes to the endothelium. 2.Transendothelial Migration: 1. After firm adhesion, leukocytes undergo a series of steps to migrate through the endothelial cell layer. 2. This process involves the coordinated action of various adhesion molecules and cytoskeletal rearrangements. 3. Once leukocytes have migrated through the endothelium, they enter the tissue space, where they can continue their immune response. 3.TCR-Associated Protein Interactions: 1. Within the immune synapse, various proteins associated with the TCR and co-receptors interact with signaling molecules and cytoskeletal elements. 2. These interactions regulate T cell activation, signal transduction, and cytoskeletal rearrangements necessary for the formation and maintenance of the immune synapse. In summary, leukocyte extravasation involves leukocytes interacting with endothelial cells via integrins such as LFA-1, followed by transendothelial migration to enter tissue spaces. The formation of an immune synapse between T cells and APCs during antigen recognition facilitates T cell activation and signaling, with interactions between TCR-associated proteins playing crucial roles in this process. When it's mentioned that the antigen-presenting cell (APC) and T cell are "PMS nearly touching," it likely refers to the initial stages of immune synapse formation, where the two cells are in close proximity but haven't formed a stable junction yet. Here's a breakdown: 1.PMS (Peripheral Membrane Surface): 1. The peripheral membrane surface refers to the outer surface of the cell membrane, where various proteins and receptors are located. 2. In the context of immune cell interactions, "PMS nearly touching" suggests that the membranes of the APC and T cell are very close to each other, almost touching. 6 2. Early Stage of Immune Synapse Formation: 1. At the early stages of immune synapse formation, the T cell and APC recognize each other through interactions between their respective surface receptors, such as the T cell receptor (TCR) on the T cell and the peptide-major histocompatibility complex (MHC) on the APC. 2. This recognition leads to the initiation of signaling events within both cells, triggering cytoskeletal rearrangements and adhesion molecule clustering. 3.Close Proximity before Stable Junction Formation: 1. Before the formation of a stable immune synapse, the T cell and APC membranes come into close proximity, allowing for initial interactions between signaling molecules and adhesion receptors. 2. This close contact facilitates the clustering of receptors and signaling molecules at the interface between the T cell and APC, laying the groundwork for the formation of a mature immune synapse. 4.Transition to Stable Immune Synapse: 1. As signaling and adhesion molecule clustering intensify, the T cell and APC membranes stabilize their interaction, forming a mature immune synapse. 2. The mature immune synapse is characterized by distinct central and peripheral regions, with concentrated TCR signaling complexes at the center and adhesion molecules like LFA-1 at the periphery. In summary, when it's mentioned that the APC and T cell are "PMS nearly touching," it indicates that they are in close proximity during the early stages of immune synapse formation, setting the stage for the establishment of a stable junction where signaling and adhesion occur in a coordinated manner. 6 Schematic of Immune Synapse Functions of the Immune Synapse: Maintains APC –CD4 helper T cell signaling to promote activation Focuses cytokine signaling between cells (esp. from T cell to cell displaying antigen) Insures specific killing of target cell by CD8+ CTLs Sure, let's break down the schematic of the immune synapse and its functions in detail: 1.Schematic of Immune Synapse: 1. The immune synapse is a specialized junction formed between an antigen-presenting cell (APC) and a T cell during antigen recognition. 2. In the schematic, the APC is depicted at the top, and the T cell is depicted at the bottom. 3. The central region of the synapse represents the interface between the APC and T cell, where key signaling and adhesion molecules are localized. 2.Key Components of the Immune Synapse: 1. Class II MHC (MHC-II): Presenting antigenic peptides to the T cell receptor (TCR) on the T cell. 2. TCR: Engaging with the antigenic peptide presented by MHC-II on the APC. 3. LFA-1 (Leukocyte Function-Associated Antigen-1): Integrin receptor on the T cell, binding to ICAM-1 (Intercellular Adhesion Molecule-1) on the APC, facilitating adhesion between the two cells. 4. PKC-θ (Protein Kinase C-theta): Signaling molecule activated downstream of TCR engagement, playing a role in T cell activation and cytokine 7 production. 3. Functions of the Immune Synapse: 1. Maintains APC-CD4 Helper T Cell Signaling: The immune synapse promotes sustained signaling between the APC and CD4+ helper T cell, leading to T cell activation. This signaling is essential for initiating immune responses against pathogens. 2. Focuses Cytokine Signaling: Cytokines, such as interleukins, are signaling molecules crucial for regulating immune responses. The immune synapse facilitates the transfer of cytokines from the T cell to the APC, enhancing communication between the two cells and coordinating immune responses. 3. Insures Specific Killing by CD8+ CTLs: In the case of CD8+ cytotoxic T lymphocytes (CTLs), the immune synapse ensures specific recognition and killing of target cells displaying antigenic peptides on MHC molecules. The formation of a mature immune synapse between the CTL and target cell facilitates the delivery of cytotoxic molecules, leading to target cell destruction. 4.Mechanism of Signaling: 1. Upon TCR engagement with the antigenic peptide-MHC complex on the APC, signaling cascades are initiated within the T cell. 2. PKC-θ, located in the central region of the immune synapse, is activated downstream of TCR signaling, contributing to T cell activation, cytokine production, and effector functions. In summary, the immune synapse plays a critical role in coordinating immune responses by facilitating signaling between APCs and T cells, focusing cytokine signaling, and ensuring specific target cell killing by CTLs. It serves as a platform for molecular interactions essential for initiating and regulating immune responses against pathogens and abnormal cells. 7 Steps of the T cell intracellular signal pathway 1. TCR binds specific peptide-MHC (“ligand”) 2. CD4 or CD8 co-receptor binds MHC 3. CD4/CD8-associated Lck phosphorylates ITAMs on CD3 & zeta chains 4. P-Tyr residues act as recruitment sites for other signaling proteins (kinases) 5. Signaling proteins lead to activation of transcription factors 6. Expressed proteins induce activation of T cell Absolutely, let's detail the steps of the T cell intracellular signaling pathway: 1.TCR Binds Specific Peptide-MHC Complex: 1. The process begins when the T cell receptor (TCR) recognizes and binds to a specific peptide antigen presented by a major histocompatibility complex (MHC) molecule on the surface of an antigen-presenting cell (APC). 2.CD4 or CD8 Co-receptor Binding: 1. Depending on the type of T cell (CD4+ helper T cell or CD8+ cytotoxic T cell), the CD4 or CD8 co-receptor binds to the MHC molecule, enhancing the stability of the TCR-MHC-peptide interaction. 3.CD4/CD8-Associated Lck Phosphorylates ITAMs: 1. The cytoplasmic tail of the CD3 complex and the ζ chain of the TCR contain immunoreceptor tyrosine-based activation motifs (ITAMs). 2. Lck, a Src family kinase associated with CD4 or CD8, phosphorylates tyrosine residues within the ITAMs upon TCR engagement. 4.Phosphorylated Tyrosine Residues as Recruitment Sites: 1. Phosphorylated tyrosine residues within the ITAMs serve as docking sites for various signaling proteins, including other kinases and adaptor molecules. 8 2. These recruited proteins initiate a signaling cascade that amplifies and propagates the TCR signaling pathway. 1.Signaling Proteins Activation of Transcription Factors: 1. The activated signaling cascade leads to the activation of downstream signaling proteins, including kinases such as ZAP-70 and MAP kinases. 2. These signaling proteins ultimately activate transcription factors such as NFAT, NF-κB, and AP-1. 2.Transcription Factor-Mediated Gene Expression: 1. The activated transcription factors translocate to the nucleus and bind to specific DNA sequences in the promoter regions of target genes. 2. This binding initiates the transcription of genes involved in T cell activation, proliferation, differentiation, and effector functions. 3.Induction of T Cell Activation: 1. The expressed proteins, which include cytokines, cell surface receptors, and effector molecules, contribute to the activation and function of the T cell. 2. These proteins mediate various immune responses, such as cytokine secretion, cytotoxicity, and the regulation of other immune cells. In summary, the T cell intracellular signaling pathway involves a series of steps initiated by TCR engagement with specific peptide-MHC complexes, leading to the activation of downstream signaling cascades, transcription factor activation, and ultimately, the induction of T cell activation and immune responses. 8 How does the adaptive immune system carry out surveillance? Large diversity of receptors Each receptor recognizes a specific target termed an “antigen” ChatGPT ChatGPT The adaptive immune system carries out surveillance by employing various mechanisms, primarily through the actions of T lymphocytes (T cells) and B lymphocytes (B cells). Here's how these cells contribute to immune surveillance: 1.T Lymphocytes (T Cells): 1. T lymphocytes play a central role in the adaptive immune response, particularly in cell-mediated immunity. 2. Each T cell expresses a unique T cell receptor (TCR) on its surface, which is generated through somatic rearrangement of gene segments during T cell development in the thymus. 3. The TCR is composed of α and β chains (or γ and δ chains in some cases) and recognizes specific antigens presented by major histocompatibility complex (MHC) molecules on the surface of other cells. 2.Stages of T Cell Development: a. Immature T Cell (A): This refers to a T cell in the early stages of development within the thymus. Immature T cells undergo positive and negative selection processes to ensure proper TCR signaling and self-tolerance. b. 9 Immature and Naïve T Cell (B): These are T cells that have completed development in the thymus but have not yet encountered their specific antigen. They are termed "naïve" because they have not been activated by antigen exposure. c. Mature T Cell (C): Mature T cells have completed their development and have exited the thymus. They are capable of recognizing specific antigens presented by MHC molecules. d. Mature and Naïve T Cell (D): These are fully developed T cells that have not yet encountered their specific antigen. They circulate throughout the body in search of antigens. e. Activated T Cell (E): These are T cells that have encountered their specific antigen and become activated. Activation leads to T cell proliferation, differentiation into effector cells, and the initiation of immune responses. 3. Function of T Lymphocytes: 1. Naïve T cells continuously survey the body for antigens presented by APCs. When a TCR on a naïve T cell recognizes its specific antigen presented by an APC, along with co-stimulatory signals, the T cell becomes activated. 2. Activated T cells undergo clonal expansion and differentiate into effector T cells, such as helper T cells (Th) or cytotoxic T cells (CTLs), depending on the type of antigen encountered. 3. Effector T cells perform various functions, including secreting cytokines to regulate immune responses (Th cells) or directly killing infected or abnormal cells (CTLs). In summary, the adaptive immune system carries out surveillance through the large diversity of T cell receptors, each recognizing specific antigens. T cells undergo various stages of development and activation, from immature and naïve states to mature and activated effector states, allowing them to respond to specific antigens encountered in the body and initiate appropriate immune responses. 9 Naïve B cells use IgM and IgD as B Cell Receptors (BCRs) Plasma cell Certainly, let's delve into the stages of maturation of B cells, their differentiation, and the roles of IgM and IgD as B cell receptors (BCRs): 1.Stages of B Cell Maturation: a. Stem Cell: B cell development begins in the bone marrow from hematopoietic stem cells. b. Pre-B Cell: Hematopoietic stem cells commit to the B cell lineage and undergo rearrangement of immunoglobulin gene segments to form functional B cell receptors (BCRs). c. Mature B Cell: B cells that have successfully rearranged their immunoglobulin genes and express surface IgM and IgD as BCRs. They exit the bone marrow and circulate in peripheral lymphoid tissues. d. Activated B Cell: Upon encountering their specific antigen, mature B cells become activated, leading to proliferation and differentiation into plasma cells or memory B cells. e. Plasma Cell (Antibody-Secreting Cell): Terminally differentiated B cells that produce and secrete large quantities of antibodies specific to the encountered antigen. f. Memory B Cell: Long-lived B cells that retain the ability to recognize and respond rapidly to previously encountered antigens upon re-exposure. 2.B Cell Receptors (BCRs): 1. BCRs are membrane-bound immunoglobulin molecules expressed on the surface of B cells. 2. Naïve B cells initially express IgM and IgD as their BCRs, which are produced through alternative splicing of the same primary RNA 10 transcript. 3. IgM and IgD have identical antigen-binding domains but different constant regions. 4. IgM is the first antibody isotype expressed during B cell development, while IgD plays a role in B cell activation and signaling. 1.Differentiation and Function: 1. Despite expressing similar BCRs, naïve B cells differentiate into distinct effector cells based on their antigen encounter and microenvironmental cues. 2. Upon encountering their specific antigen, B cells become activated and differentiate into plasma cells or memory B cells. 3. Plasma cells specialize in antibody secretion, while memory B cells persist in the body to mount faster and stronger responses upon re-exposure to the same antigen. 2.Activation and Antibody Production: 1. When a naïve B cell encounters its specific antigen, the antigen binds to the BCR, triggering B cell activation. 2. Activated B cells proliferate and differentiate into plasma cells, which are highly specialized in antibody production. 3. Plasma cells produce large quantities of antibodies specific to the encountered antigen, which are then released into the bloodstream to eliminate pathogens and contribute to immune responses. In summary, the maturation of B cells involves a series of developmental stages from stem cells to plasma cells or memory B cells. Naïve B cells express IgM and IgD as BCRs and differentiate into effector cells upon encountering their specific antigen, leading to antibody production and immune responses. Despite their initial similarity, B cells differentiate into distinct effector cells with specialized functions based on their antigen encounter and microenvironmental signals. 10 BCR-initiated signal pathway Binding to antigen Initiates pathway An individual B cell expresses receptors for a single antigen Forms a complex with Iga and Igb proteins Iga- and Igb-associated kinases activated by antigen binding P-Tyr recruits signaling proteins => TFs activated Expression of proteins that induce B cell activation Sure, let's break down the BCR-initiated signal pathway in detail: 1.Binding to Antigen Initiates Pathway: 1. When a B cell encounters its specific antigen, the antigen binds to the B cell receptor (BCR), which consists of membrane-bound immunoglobulin (IgM or IgD) molecules. 2. This binding initiates a signaling pathway within the B cell, leading to activation and subsequent immune responses. 2.Individual B Cell Expresses Receptors for a Single Antigen: 1. Each B cell expresses BCRs specific to a single antigen due to the random rearrangement of immunoglobulin gene segments during B cell development. 2. This ensures that each B cell can recognize a unique antigen and mount a specific immune response against it. 3.Formation of Complex with Igα and Igβ Proteins: 1. The Igα (CD79a) and Igβ (CD79b) proteins are associated with the BCR complex and play essential roles in B cell signaling. 2. Upon antigen binding, the BCR forms a complex with Igα and Igβ, facilitating signal transduction. 4.Activation of Igα- and Igβ-Associated Kinases: 11 1. Antigen binding to the BCR leads to the activation of kinases associated with Igα and Igβ, such as Lyn kinase. 2. These kinases phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) within the cytoplasmic tails of Igα and Igβ. 1.Phosphorylation of ITAMs: 1. Phosphorylation of ITAMs serves as a signal for downstream signaling events. 2. Phosphorylated ITAMs act as docking sites for signaling proteins, such as Syk kinase, leading to further signal amplification. 2.Recruitment of Signaling Proteins and Activation of Transcription Factors: 1. Phosphorylated ITAMs recruit signaling proteins to the BCR complex, leading to the activation of downstream signaling pathways. 2. These signaling pathways culminate in the activation of transcription factors, such as NF-κB and AP-1, which translocate to the nucleus and initiate the transcription of genes involved in B cell activation and proliferation. 3.Expression of Proteins that Induce B Cell Activation: 1. The activated transcription factors drive the expression of proteins that promote B cell activation, proliferation, and differentiation. 2. These include cytokines, cell surface receptors, and proteins involved in antibody production and immune responses. In summary, the BCR-initiated signal pathway begins with antigen binding to the BCR and proceeds through a series of steps, including the formation of a complex with Igα and Igβ, activation of kinases, phosphorylation of ITAMs, recruitment of signaling proteins, activation of transcription factors, and expression of proteins that induce B cell activation and immune responses. 11 Maturation and Activation of Lymphocytes Plasma cell The maturation and activation of lymphocytes, including T cells and B cells, rely on various signaling pathways that detect and respond to specific molecular cues. Here's how these signaling processes work: 1.Basics of Maturation: 1. Lymphocyte maturation refers to the process by which immature lymphocytes develop into mature, functional cells capable of mounting immune responses. 2. In T cell maturation, precursor cells from the bone marrow migrate to the thymus, where they undergo positive and negative selection processes to ensure functional T cell receptor (TCR) expression and self-tolerance. 3. B cell maturation occurs in the bone marrow, where B cell precursors undergo V(D)J recombination to generate diverse B cell receptors (BCRs) capable of recognizing a wide range of antigens. 2.Detection of Maturation Signals: 1. Maturation signals are detected by specific receptors and signaling pathways that respond to environmental cues within the thymus or bone marrow. 2. In the thymus, T cell maturation signals are mediated by interactions between developing thymocytes and stromal cells expressing thymic 12 epithelial cell markers. 3. B cell maturation signals involve interactions between developing B cells and stromal cells within the bone marrow microenvironment, as well as signals from cytokines and growth factors. 1.Basics of Activation: 1. Lymphocyte activation refers to the process by which mature lymphocytes become functionally activated in response to encountering their specific antigen. 2. T cell activation typically involves recognition of peptide antigens presented by antigen-presenting cells (APCs) in the context of major histocompatibility complex (MHC) molecules. 3. B cell activation occurs when the BCR binds to its cognate antigen, leading to signaling events that promote B cell proliferation, differentiation, and antibody production. 2.Detection of Activation Signals: 1. Activation signals are detected by receptors and signaling molecules on the surface of lymphocytes that recognize antigens or antigen-presenting cells. 2. T cell activation signals are transmitted through the TCR complex, coreceptors (such as CD4 or CD8), and co-stimulatory molecules (such as CD28). 3. B cell activation signals are transmitted through the BCR complex, coreceptors (such as CD19 and CD21), and co-stimulatory molecules (such as CD40). 3.Signal Transduction Pathways: 1. Both maturation and activation signals are transmitted through intracellular signal transduction pathways, which involve a series of molecular events that amplify and propagate the initial signal. 2. These pathways typically involve phosphorylation cascades, activation of transcription factors, and regulation of gene expression, leading to changes in cell behavior and function. In summary, the maturation and activation of lymphocytes rely on the detection of specific signals through receptors and signaling pathways. These signals regulate key processes such as thymic selection, BCR and TCR signaling, and activation-induced gene expression, ultimately leading to the development of mature, functional lymphocytes capable of mounting effective immune responses. 12