Fortress Body V: Cell-Mediated Immunity PDF

11/11/23 Fortress body V: cell-mediated immunity: Learning objective: de ne the role of T cells in cell mediated immunity. Learning objective: understand the process of T cell differentiation and T cell selection. Learning objective: de ne the difference bet ween CD4+ and CD8+ T cells. Learning obje...

11/11/23 Fortress body V: cell-mediated immunity: Learning objective: de ne the role of T cells in cell mediated immunity. Learning objective: understand the process of T cell differentiation and T cell selection. Learning objective: de ne the difference bet ween CD4+ and CD8+ T cells. Learning objective: understand the principle of T cell regulation by cytokines. Learning objective: de ne Th1, Th2, Th17 and T-reg cell types and their function. T cell development: Precursors are lymphoid progenitors, derived from bone marrow. Migrate to the thymus, where they mature. Rearrange T cell antigen receptor genes randomly to give a vast range. Many of these react strongly with south antigens and are deleted. Generation of T cell repertoire: In the thymus, T cell precursors rearrange T cell receptor variable, diversity, and joining gene segments randomly for both alpha and beta receptor chains. This gives rise to a huge repertoire of cells with different receptor speci cities. All receptor proteins on any one lymphocyte have the same epitope speci city. T cell maturation: The thymus is made up of the inner section ( medulla ) and the outer core. In order to become mature, the T cells develop as thymocytes. These interact with stromal cells which leads to their activation as they pass through the thymus. This interaction ( stromal and thymocytes ) gives rise to alpha-beta T cells. The earliest developing thymocytes lack the expression of the CD4 and CD8 co-receptors and these cells are called double negative cells ( DN as shown in the diagram ). This DN population can be subdivided, by expression of surface markers. Cells that lack the expression of CD44 but express CD25 are termed DN3 cells. DN3 cells undergo beta selection. This process selects for the cells that have successfully rearranged the DNA that codes for the T cell receptor beta chain. The beta chain then pairs with a pre alpha chain and produces a pre T cell receptor complex. This then forms a complex with CD3 molecules. CD3 is a common surface marker for all T cells. The interaction bet ween the pre T cell and the CD3 leads to survival and proliferation as well as an arrest in further beta chain arrangement. These cells then undergo further differentiation by up-regulation and expression of CD4 and CD8. We call these double positive cells. So these double positive cells that express CD4 and CD8 and the T cell receptor, then undergo a process where they rearrange the T cell receptor alpha chain to produce a mature alpha beta T cell receptor. The double positive thymocytes, then migrate into the medulla to undergo this process of negative selection, which is where they are presented to self antigens on MHC on APCs and if they interact too strongly they are killed. Following this process, the cells then down regulate expression of one of the core receptors, so the CD4 or CD8 and then they become naive CD4+ or CD8+ cells. Diagram summarising: pro tous tm thymocytes 18g activated P tour x dable negative T cells DN 2 88 so DN2 1 DN3 is chain ppresent Igg pre i cenrecepto complex 18 survival t proliferation ArrestinPanther 88 B chainrearrangement g8a d able positive cen s 858g u mature a p tous dregselection mature x P our Downreg d CDGCD4 NaiveCDstarCbat T cells T cell recognition: Unlike B cells, T cells cannot recognise free antigen. They recognise antigens via T-cell receptor in the form of short peptides presented by MHC. This is through the antigen-presentation by antigen presenting cells or virus infected cells. T cell activation: In peripheral lymphoid tissue. Mature T cells encounter speci c antigen, presented by antigen presenting cells and become activated. This induces proliferation/ clonal expansion and differentiation of antigen speci c T cells into effector cells and memory cells. fitocrine Activated cytotoxic T cells secrete: 1. Perforin: forms pores in the membrane of infected cells. 2. Granzymes: cause apoptosis. 3. Granulysin: antimicrobial activity- contributes to apoptosis. Secrete cytokines to attract macrophages and other immune cells. Degraded cells rapidly removed by macrophages. Functions of Helper T cells: These work largely by secreting cytokines. Cytokines communicate with other immune cells and activate other effector cells to eliminate the pathogens by appropriate immune responses. Different T helper subsets secrete different cytokines. Helper T cell differentiation and subsets: Once activated, they differentiate into different subsets secreting different cytokines. Different combinations of cytokines depending on type of response that’s needed. So each particular combination of cytokines will activate different transcription factors within that naive T cell. These transcription factors will initiate the expression different genes that will lead to the differentiation of that naive T cell into one of the following: Th1, Th2, Th17 or a T-reg cell. Th1 response: Intracellular infection. Promote growth and differentiation of other T cells ( IL-2 ). Activation of macrophages and enhanced phagocytosis (.IFN ). y Regulates MHC expression. Stimulates production of antibodies. Th2 response: Parasitic infection. Stimulates B cells for IgE antibody production and activates mast cells and eosinophils to release toxic molecules to kill parasites. Induces production of mucus in intestines. Th17: Infection by extra cellular bacteria or fungi. Stimulate endothelial cells, broblasts, macrophages to produce antimicrobial peptides and cytokines. Indirectly recruit neutrophils to infection sites. T-reg cells: Treg cells balance the pro-in ammatory response. They suppress T cell responses and limit in ammation. They prevent autoimmunity. Potent suppression of macrophage function. Induces generation of more T-Reg cells. switch off everything infection cleared when