Key learning outcomes_Adaptive Immunity_Lectures_Pepper_2023.pdf

Key learning outcomes – things you should know Adaptive immunity lectures – Chris Pepper Adaptive immunity 1 - What is the adaptive immune system, what does it do and why do we need one? You should know: • that B- and T-lymphocytes are the key cellular components of the adaptive immune system • how...

Key learning outcomes – things you should know Adaptive immunity lectures – Chris Pepper Adaptive immunity 1 - What is the adaptive immune system, what does it do and why do we need one? You should know: • that B- and T-lymphocytes are the key cellular components of the adaptive immune system • how to identify B cells and T cells using immunophenotyping; B cells express CD19, CD20, T cells express CD3 and either CD4 (T helper) or CD8 (cytotoxic T cell) • how B cells and T cells develop. Both cell types are created in the bone marrow; B cells continue to mature in the bone marrow, T cell progenitor cells migrate to the thymus where continue to differentiate. Both cell types undergo positive and negative selection; positive selection identifies cells that can bind antigen (in the case of T cells, MHC-bound peptide) and signal through their receptor (B cell receptor or T cell receptor) – the signalling promotes their survival. Negative selection involves the binding of self-antigen to the B cell receptor or T cell receptor, which results in deletion of the cell by apoptosis· • how B cells and T cells generate an immune response. B cells can recognise native antigen e.g. micro-organisms. T cells need antigen to be processed into peptides and presented to them in the context of MHC molecules – CD4 T cells recognise MHC II and CD8 T cells recognise MHC I. • B cells take up antigen through the specific binding to their B cell receptor. Other antigen presenting cells are capable of recognising a large range of pathogens via their pattern recognition receptors (e.g. TLRs, CLRs, NLRs, RLRs). In all cases, the bound receptor is internalised through the process of endocytosis and the endosomes (phagosomes) then bind to lysosomes, which create a highly acidic environment resulting in proteolytic degradation of the pathogen. The peptides are subsequently complexed with MHC II molecules and trafficked to the cell surface where they are presented to CD4 T cells. The recognition of the MHC II-bound peptide by a CD4 T cell results in a cascade of events leading to full activation of both the presenting B cell and the T cell. • Most antigens recognised by B cells (and other antigen presenting cells) require T cell help in order to generate an immune response. Some antigens (e.g. bacterial polysaccharides) can trigger B cell receptor cross linking and the production of antibodies (usually non-class switched IgM) without T cell help (T-independent). • T-dependent responses require antigen presentation in the context of MHC molecules and T cell receptor recognition. The activation is reinforced by a second signal following the binding of CD40L (on T cells) with CD40 (on B cells); the binding of co-stimulatory molecules (CD80 and CD86 on B cells; also known as B7.1 and B7.2, respectively) and CD28 (on T cells) provides a second activation signal to the T cell. T cell secreted cytokines (e.g. IL-4) provide the third activation signal to the B cells. • Antigenic challenge of the adaptive immune system results in immunological memory. This is important as it allows faster and more effective responses to repeat exposure to antigen. 1 Adaptive immunity 2 - the nuts and bolts of diversity - somatic hypermutation, affinity maturation and class switch recombination You should know: • • • • The primary mechanism for generating immune cell diversity is through the process of VDJ recombination – this is the genetic recombination of a variable region with a diversity region and a joining region. This process occurs in both B cells (immunoglobulin gene) and T cells (T cell receptor gene) and generates a vast array of different B cell receptors and T cell receptors. The key enzymes responsible for this process are the recombination-activating genes, RAG-1 and RAG-2 In the case of B cells, further refinement of B cell receptor recognition of antigen occurs via a process called somatic hypermutation. The critical enzyme involved in this process is activation-induced cytidine deaminase (AID). Antibody class switching, or class switch recombination is the last step in a B cell’s response to antigen. The class switching does not affect the affinity of the B cell receptor for antigen but instead replaces the constant region of the antibody so that it can interact with different effector molecules. The process of class switching is mediated by a process of DNA breakage and recombination Naïve B cells express two alternative isotypes of immunoglobulin, IgM and IgD. These two alternative classes of immunoglobulin are not produced by class switch recombination as the naïve B cell has not yet experienced antigen. Instead, both IgM and IgD are produced by alternative mRNA splicing due to the close proximity of the µ and d constant regions in the immunoglobulin gene structure. Adaptive immunity 3 - antigen processing, presentation and recognition You should know: • why T cells need to work with antigen presenting cells • That there are two alternative pathways for antigen processing; the exogenous pathway and endogenous pathway • That exogenous antigens e.g. pathogens are processed via the exogenous antigen presentation pathway. This pathway involves the endocytosis of the pathogen and the subsequent breakdown of its proteins into peptides in a phagolysosome. These peptides are complexed with MHC II molecules and shuttled to the cell surface where they are presented to CD4+ T cells • That endogenous antigens are broken down in the proteasome before being transported via the TAP proteins to the endoplasmic reticulum. They are complexed with MHC class I molecules in the golgi prior to presentation on the cell surface to CD8+ T cells • MHC class II complexed peptides are recognised by CD4+ T cells and MHC class I complexed peptides are recognised by CD8+ T cells 2