Lecture 13 - Immunology Study Guide PDF

Lymphocyte maturation involves: 1. Commitment of progenitor cells to either the B lymphoid or T lymphoid lineage 2. Proliferation of progenitor cells and immature committed cells 3. Sequential rearrangement (recombination) of antigen receptor chains 4. Selection of cells expressing functional antige...

Lymphocyte maturation involves: 1. Commitment of progenitor cells to either the B lymphoid or T lymphoid lineage 2. Proliferation of progenitor cells and immature committed cells 3. Sequential rearrangement (recombination) of antigen receptor chains 4. Selection of cells expressing functional antigen receptors & elimination of cells that strongly recognize self antigens 5. Differentiation of B and T cells into distinct subpopulations 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: 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 1 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. 1 Selection and Elimination Occurs at Checkpoints Cells that fail to meet requirements of checkpoint will undergo apoptosis - proliferation- means more cells - First check 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 -à 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) ChatGPT ChatGPT 2 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 nonfunctional 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 2 with non-functional receptors are eliminated to maintain the integrity and effectiveness of the immune system. 2 Checkpoint 2 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 -à clonal deletion But B cells may undergo further rearrangements ---> receptor editing 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: 3 1. Negative selection, also known as central tolerance, is a critical mechanism for eliminating autoreactive lymphocytes that recognize selfantigens too strongly. 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. 3 a, d, e, g, µ = HCs A, D, E, G, M Key events in B cell maturation k, l = LCs Two rounds Sequential rearrangement Change as maturation proceeds 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). 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. 2.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. 4 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. 1.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. 2.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? 4 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 and thus one unquie antigen receptor 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 5 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 receptor specificities. 1.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. 2.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. 5 Key events in T cell maturation Thymocytes = Developing T cells in the thymus Like B cell maturation in many ways but critical differences exist Sequential rearrangement Change as maturation proceeds 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: 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. 2.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. 6 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. 1.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. 2.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. 3.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. 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. 6 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 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). 7 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. 1.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. 2.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. 3.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. 4.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. 7 T cell development in the thymus From bone marrow See Figure 2.12 (p. 31) for a description of thymus morphology (if interested) Pro-T 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 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. 3.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 8 molecules receive survival signals and progress to become mature T cells. 4. 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. 5.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. 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 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. 8 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 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. 8