Adaptive Immunology - UM1011

ADAPTIVE IMMUNOLOGY Dr G O’Connor [email protected] HA240  Adaptive Immunology Lesson Plan Feature of adaptive immunity Antigen presentation Lymphocyte activation B cell effect...

ADAPTIVE IMMUNOLOGY Dr G O’Connor [email protected] HA240  Adaptive Immunology Lesson Plan Feature of adaptive immunity Antigen presentation Lymphocyte activation B cell effector function T cell effector function Memory Adaptive Immunity  Phases of Adaptive Immunity Antigen is any molecule that is specifically recognised by lymphocytes or antibodies Naive lymphocytes are mature T or B cells that have never encountered foreign antigen T and B cells bind to specific antigens. This leads to activation, proliferation and differentiation of these cells (this takes time).  Functions of Adaptive Immunity Adaptive Immunity is mediated by T cells and B cells. B cells mediate humoral (soluble) immunity through the production of antibodies Helper T cells interact with other immune cells to orchestrate an effective immune response Cytotoxic T cells can kill host cells that are infected or malignant  Memory in the Adaptive Immunity After the resolution of the infection, some cells remain that respond faster the next time – i.e. memory cells This may prevent infection, or lessen the severity of the disease TCR and BCR  Recognition of Antigen B cells express a B cell receptor (BCR) and T cells express a T cell receptor (TCR), which allow them to recognise (foreign) antigen The BCR can directly recognise an antigen, The TCR cannot directly recognise an antigen. Proteins must be processed into peptides and presented in MHC before T cell recognition ANTIGEN PRESENTATION  Antigen Presentation I T cells cannot recognise foreign proteins directly. To recognise these proteins, they must be processed into peptides and bound to self-molecules known as the major histocompatibility complex (MHC). In humans this is also known as Human Leukocyte Antigen (HLA). T cells need to recognise foreign protein 1. From intracellular pathogens, where the foreign protein is made by a host cell – MHC Class I pathway 2. From pathogens that are extracellular – MHC Class II pathway  Antigen Presentation Class I and Class II MHC Class I MHC Class II  MHC Class I Pathway Foreign proteins that end up in MHC class I are made in the presenting cell. These MHC molecules are recognised by cytotoxic T cells. These cells have the marker CD8 which acts as a co-receptor for MHC class I The consequence is death of presenting cell  MHC Class II Pathway Foreign proteins that end up in MHC class II have been taken up by presenting cell. These MHC molecules are recognised by helper T cells. These cells have the marker CD4 which acts as a co-receptor for MHC class II The consequence is activation of the helper T cell  MHC Pathways Protein made in the cell e.g. virally infected cell Protein taken up from outside the cell e.g. phagocytosis MHC Class I Expressed on all nucleated cells There are 3 classical MHC Class I genes in humans, encoded on chromosome 6. HLA-A, HLA-B and HLA-C. They are the most polymorphic genes in the human genome. Variants of each gene denoted by number e.g. HLA-B*0701, HLA- B*2705, and differ in their peptide- binding characteristics MHC Class II MHC Class II is expressed by antigen-presenting cells of the immune system. This includes dendritic cells, but also macrophages and B cells. There are six main MHC class II genes in humans: HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA- DQB1, HLA-DRA, and HLA- DRB1 They are very polymorphic genes. Dendritic Cells (DCs) DCs play a central role in processing and presenting antigen i.e. they are professional antigen presenting cells (APCs). Macrophages and B cells also act as APCs. DIVERSITY OF TCR AND BCR  BCR/Antibody Structure Each BCR/antibody molecule is composed of 2 identical heavy chains (H) and 2 identical light chains (L), which are held together by disulphide bonds (s-s). Each chain contains constant (C) and variable (V) regions. Light: 1 C domain, 1 V domain Heavy: 3-4 C domain, 1 V domain  TCR Structure The TCR consists of two chains (typically α and β), held together by a disulphide bridge (s-s). Each chain consists of 2 domains – one constant (C) and one variable (V). The region that interacts with the antigen is formed from the V domains of both the α and β chain  TCR and BCR Diversity The variable domains of both the BCR and TCR are generated via recombination of gene segments – this gives rise to a very large number of different receptors from a limited number of gene segments  Negative Selection Random generation of BCRs and TCRs from gene segments means that some will be capable of recognition of self- antigens. In the thymus, immature T cells that recognise MHC molecules expressing self-peptides undergo apoptosis in a process of negative selection. In the bone marrow, B cells may undergo receptor editing (retry recombination) or apoptosis ACTIVATION OF ADAPTIVE CELLS  T Helper Cell Activation APC are activated to produce costimulatory molecules and cytokines by PRR engagement. B7 Recognition of antigen in the absence of signal 2 and 3 does not lead to activation Three signals: 1. TCR - Antigen recognition, 2. Co-stimulation by presenting cell 3.Cytokine Result: Clonal expansion and differentiation Signals for T cells Activation  Signal 1: BCR (membrane-bound antibody) Signals for B recognises antigen cell Activation Signal 2: Co-stimulation from Helper T cell Signal 3: Cytokines  B cell activation After recognition of antigen by BCR, the complex is internalised and processed via the MHC Class II. Recognition of this MHC- peptide by the TCR on an activated Helper T cell allows for co-stimulation and full B cell activation This happens with T- dependent protein antigens  B cell- T cell interactions Co-stimulation is due to CD40L on the activated Helper T cell and CD40 on the B cell. Cytokines produced can influence the type of antibody produced LYMPHOCYTE TRAFFICKING Lymphoid Tissue Primary (generative) lymphoid tissues are where immune cells are generated and mature - Bone marrow and thymus Secondary (peripheral) lymphoid tissue is where lymphocytes interact with antigen and become activated - Lymph nodes; Spleen; Mucosal-associated lymphoid tissue (MALT) Abbas, A. K., Lichtman, A. H., & Pillai, S. (2014). Cellular and molecular immunology E-book. Elsevier Health Sciences.  Trafficking Antigens from the tissue are delivered in the lymphatics to the lymph node. Antigens in the blood are delivered to the spleen. Lymph Node Lymph nodes: Encapsulated organs found throughout the body. Ag from the periphery is moved here through lymphatics by antigen presenting cells such as dendritic cells. Lymphoid follicles (collection of T and B cells) in the node on encountering their specific Ag will proliferate generating a germinal center that leads to the formation of fully mature, effector T and B cells. The Spleen Spleen: Encapsulated, highly vascular organ that filters blood. Is responsible for eliminating blood-borne pathogens. Also has follicles that on encountering their specific antigen will proliferate generating a germinal center that leads to the formation of fully mature, effector T and B cells EFFECTOR FUNCTIONS OF ADAPTIVE LYMPHOCYTES B Cell Function Plasma cell Antibody Isotypes There are 5 different classes or isotypes of antibody IgG (4 genes) IgA (2 genes) IgE IgM (IgD) Different classes of antibodies have different constant (Fc) regions, and may be better able to mediate different biological functions e.g. complement fixation. IgM is the first antibody produced  Antibody Isotype Switching Depending on signals, B cells can undergo isotype switching i.e. change from making IgM (first one made) to either IgG, IgE or IgA Abbas, A. K., Lichtman, A. H., & Pillai, S. (2014). Cellular and molecular immunology E-book. Elsevier Health Sciences.  Antibody Isotype Differences Role of Antibodies Antibodies are produced by the adaptive immune system but many of the effector function rely on innate immune mechanism e.g. complement, phagocytosis, NK cells.  Antibodies: Neutralisation Antibodies: Opsonisation  Antibodies: ADCC Natural Killer cells express an Fc receptor (CD16) that allows recognition of antibody-coated cells and leading to killing of these cells T cell Function  Cytotoxic T Cells TCR (CD8) Mechanism of cytotoxicity is similar to NK cells  T Helper Cells Depending on the environment (esp. cytokine) during T helper cell activation, different types of effector cells can be generated. Treg cells inhibit immune response via a variety of mechanisms including the production of IL-10 and TGF-β. They are important in maintaining self-tolerance T Helper Cell Subsets MEMORY Memory Lymphocytes Most lymphocytes generated through clonal expansion in an immune response will eventually die. However, a significant number of activated antigen-specific B cells and T cells persist after the antigen has been eliminated. They can be reactivated much more quickly than naïve T or B cells can be activated.  Primary and Secondary Immune response Second Response Secondary responses – much less antigen required and generates a more rapid response to a higher magnitude This capacity forms the basis of vaccination.