T-B Cell Interactions PDF

T – B Cell Interactions POD 233 Immunology Lecture 10 Fall 2024 Dr Garwin Kim Sing  Learning Objectives 1. To describe the difference between T-dependent and T- independent antibody production 2. To describe the process of T cell help for B cell antibody production....

T – B Cell Interactions POD 233 Immunology Lecture 10 Fall 2024 Dr Garwin Kim Sing  Learning Objectives 1. To describe the difference between T-dependent and T- independent antibody production 2. To describe the process of T cell help for B cell antibody production. 3. To understand the process of isotype switching. 4. To understand the process of affinity maturation and clonal selection. 5. To understand the function of Activation-Induced Deaminase (AID) 6. To describe the nature of plasma cells  Distinct Subsets of B Cells Respond Preferentially to Different Types of Antigens  B-1 cells which are derived from the fetal liver are self-renewing in adulthood where they populate the peritoneum and mucosa. They express a limited antibody repertoire compared to follicular B cells and marginal zone B cells of secondary lymphoid organs. They  Marginal spontaneously zone B cells are asecrete IgM antibodies that can react with microbial subset polysaccharides of bone and lipids marrow-derived B without requiring prior antigenic stimulation. cells These and in the spleen are called lymph natural nodes. antibodies. They are similar to B-1 cells – they producing antibodies with limited antigen recognition diversity, the ability to respond to polysaccharide B2 antigens and to generate natural Cells B1 antibodies. They respond quickly to Cells blood-borne microbes and differentiate into short-lived IgM- secreting plasma cells. B2  Follicular B cells (B-2 cells). The Cells most common type of antibody- producing lymphocytes circulating  Stages in Antigen-Specific B Cell Development: Overview 1. When a protein antigen is introduced into the body e.g. a vaccine, an antibody response is generated within 3-7 days after antigen exposure. 2. Naïve B lymphocytes displaying IgM and IgD receptors encounter antigen in the secondary lymphoid organs.  The Lymph Node  B and T cells are located in distinct areas of the cortex – the B cell zones and the T cell zones.. This ensures that each lymphocyte is in close contact with its appropriate APC- T cells with DCs and B cells with follicular dendritic cells (FDCs).  The lymphoid follicles are the B cell zones. Some follicles contain germinal centres (GCs) which consist of a packed centre containing actively proliferating B cells and a lighter periphery containing non-proliferative cells undergoing affinity maturation. The GCs consist of activated B cells differentiating into plasma cells and memory cells.  Follicles without GCs are called primary follicles. They are composed of rapidly dividing plasmablasts actively producing antibody.  Situated around the follicles is the parafollicular cortex containing lymphocytes, dendritic cells and  Antigen Presentation to B cells  Once IgM/IgD-expressing naïve B cells leave the bone marrow, they circulate through the blood circulation and lymphatics migrating through the spleen and lymph nodes searching for antigen.  Within the lymphoid follicles are FDCs. These are specialized, non- phagocytic stromal cells which capture and display opsonized (by antibody and/or C3b, C4b) antigens to the follicular B cells.  Antigen is presented by specialized macrophages and follicular dendritic cells (FDCs). The macrophages capture antigen (cells, proteins, molecules) from the lymph and transport them to the follicular B cells.  Differentiation from naïve to effector cell requires co-stimulatory signals, either from engagement of PRRs or signals from TFH cells.  But these two types of co-stimulatory signals are not optimal for full B cell activation. For the ability of the B cell to produce the full range of isotypes and generate memory B cells, it requires: 1. Help from T helper cells 2. CD40-CD40L interactions  Antibody Production by B Lymphocytes to T-dependent Antigens  For a protein antigen to stimulate an antibody response, B lymphocytes and TH cells also specific for that antigen must come together in lymphoid organs and interact in such as way as to stimulate B cell proliferation and differentiation into antibody- producing cells.  Questions: 1. Given that a naïve T cell specific for that antigen is rare, and a naïve B cell specific for the same antigen is rare, how do they find each other? 2. How do TH cells specific for the same antigen as a B cell only provide help to that particular B cell, and not to other nearby B cells with different specificities? 3. What is the nature of this help? Sequence of T cell-Dependent B Cell Stimulation I 1. Naïve T cells are activated in the T cell zone by antigen presented by DCs causing them to produce cytokines and express CD40L. 2. Naïve B cells in the follicles are activated by the same antigen (whole protein) which has been transported there. These B cells then move out towards the edges of the follicles (marginal zone) where activated TH cells have also migrated, both attracted to Sequence of T cell-Dependent B Cell Stimulation II 2. Protein antigens taken up by the B cells by endocytosis are presented on class II MHC to TH cells. Some of these peptides are the same as those presented to the naïve TH cells by DCs which activated them to 4. The CD40L-CD40 interaction also become effector cells in the stimulates heavy-chain isotype T cell zone. switching and affinity maturation in the germinal centre. 3. On activation, TH cells differentiate into TFH cells. They express CD40 ligand (CD40L) which engages CD40 on antigen-stimulated B cells inducing them to proliferate and increase the synthesis and secretion of Ig. T-B Cell Activation: The Hapten Carrier Effect  Protein antigens recognized by specific B cells are endocytosed and processed to generate peptides for presentation to effector T cells on Class II MHC.  These antigens are the same proteins as the ones originally processed and presented by DCs to the naïve T cell. This is called linked  So a B cell recognizes one recognition. epitope of an intact antigen and displays different epitopes for  A protein antigen that elicits a T- recognition by T cells. dependent B cell response therefore makes use of at least  This is similar to the hapten- two epitopes when activating B carrier effect where a B cell cells – an external peptide recognizes the hapten but recognized by the BCR on the presents different processed Sequence of T cell-Dependent B Cell Stimulation III 2. The initial T-B interaction, which occurs outside the lymphoid follicles, results in the production of low levels of antibodies which may be of switched isotypes, but are generally of low affinity. 4. The generation of TFH is dependent on a 3. The plasma cells generated receptor called inducible in these extra-follicular foci costimulatory (ICOS) expressed on are generally short-lived and the TFH cell which binds ICOS-L on the B produce antibodies for only a cell. few weeks. These are called These TFH cells may secrete TH1, TH2 or plasmablasts. TH17 cytokines, depending on the original antigenic stimulus. 4. Meanwhile some of the activated TH cells move into A few of the activated B cells from the the adjacent follicles to extrafollicular areas migrate back into the become follicular helper T lymphoid follicle together with the TFH Isotype Switching  In T-dependent responses, some of the progeny of activated IgM and IgD- Isotype Switching expressing B cells undergo heavy chain isotype (class) switching which is driven by signals generated by TFH cells such as cytokines and CD40-CD40L interactions.  B cells change the isotypes of the antibodies they produce by changing the constant regions from Ig or Ig to Ig,  or  without changing the antibody specificity (Variable region).  IFN induces the switch to IgG while IL-4 induces the switch to IgE. And B cells in the mucosa produce mainly IgA, driven in a large part by TGFβ.  CD40 signals work together with cytokines to induce isotype switching, by activating a key enzyme activation-induced deaminase (AID) which is also crucial for affinity maturation. Affinity Maturation  Affinity Maturation: Somatic Mutation of Ig Genes and Selection of High Affinity B Cells 1. Affinity maturation is the process that leads to increased affinity of antibodies for a particular antigen as a T-dependent humoral response progresses, generating antibodies with an increased ability to bind antigens and thus to more efficiently neutralize and remove microbes. 2. It only occurs after repeated exposure to T cell-dependent protein antigens and is driven by signals from TFH cells such as cytokines and CD40-CD40L 3. V genes of germinal centre lymphocytes undergo somatic hypermutation (SHM). 4. Note: (1) These mutations are clustered in the V regions. (2) There are more mutations in IgG than IgM antibodies 5. During proliferation of the follicular B cells following antigen exposure, the new cells undergo high rates of mutation in the CDR hypervariable regions. The enzyme AID is responsible for much of this mutation. Those mutations giving the strongest signals for growth and survival for clones  Generation of Memory Cells  Memory B cells to T cell-dependent antigens are generated in the germinal centres of secondary lymphoid organs. They are capable of making rapid responses to subsequent introduction of antigen.  They survive for very long periods without requiring antigenic stimulation.  Some memory cells remain in the lymphoid organ where they were generated whereas others recirculate between the blood and lymphoid organs.  Effective vaccines against microbes and microbial antigens must induce both affinity maturation and memory B cell formation, events that can only occur with T cell help. Some vaccine targets such as capsular polysaccharide are T cell- independent, activating B1 cells. In these cases, the capsular antigen is covalently linked to a foreign protein to generate a good T cell response, similar to a hapten-carrier conjugate. So these are called conjugate vaccines. Summary  Features of B Cell Activation  The type and amount of antibodies produced varies according to:  The type of antigen driving the immune response  The involvement of TFH cells  A prior history of antigen exposure  The anatomic site where activation occurs  High affinity antibody responses of different isotypes to protein antigens require that the antigenic proteins be taken up by the B cells and presented to T FH cells. These TFH cells in turn provide help to B cells in the formation of germinal centres. Follicular dendritic cells are also involved in this process.  Antibody responses to multivalent non-protein antigens with repeating determinants such as polysaccharides, some lipids and nucleic acids to not require T cell help. These are T-independent antigens.  Primary and secondary antibody responses to protein antigens differ both  B Cell Differentiation Memory Cell (Long-Lived; Responds Rapidly to Secondary Naïve B Plasmabl Exposure to Antigen cell ast Plasma Cell (Actively Produces Antibody; Non- dividing)  Reading Material  Abbas et al., Basic Immunology: Functions and Disorders of the Immune System  Cyster, JG. And Allen, CDC. B cell responses: Cell interaction dynamics and decisions. Cell 177:524- 540, 2019.