T Cells Lecture 1 PDF

T cells lecture 1 Emily Gwyer Findlay SGH  Learning outcomes Understand how T cells develop, and how their development controls their function Learn how to distinguish between CD4 and CD8 T cells, and understand how their functions differ Explain how T cells identify pathogens...

T cells lecture 1 Emily Gwyer Findlay SGH  Learning outcomes Understand how T cells develop, and how their development controls their function Learn how to distinguish between CD4 and CD8 T cells, and understand how their functions differ Explain how T cells identify pathogens, foreign cells and infected cells Describe how T cells eliminate infected cells or foreign cells Innate vs adaptive immunity Innate Immunity Adaptive Immunity Immediate response to Gradual response, pathogens building over days Targets groups of Targets specific pathogens through TLR pathogens Limited diversity of Highly diverse antigen antigen receptors receptors No memory of pathogens Produces immunological memory Innate vs adaptive immunity  Do we need T cells? We do need adaptive immunity. Babies born with severe combined immunodeficiency (SCID) from one of nine gene mutations have no adaptive immunity. They have a life expectancy of approx. one year if not treated with gene therapy. They suffer continued bacterial / fungal / viral infections Fingolimod can be used to model the importance of T vs B cells. This is a new drug for autoimmune disease which blocks the movement of T cells out of lymph – so there are no T cells at all in tissues or in peripheral blood  Do we need T cells? Virus infection of the white matter of the brain T cells – the cellular arm of the adaptive immune response T stem cells are generated in the bone marrow, before they move to the thymus to mature A long and convoluted maturation process generates an ENORMOUS diversity of T cell receptors (TCR) on the surface of T cells. This enables recognition of millions of amino acid sequences as foreign; following this recognition the T cells begin an immune response Their effector functions are: killing cells directly; helping B cells make antibody; producing large amounts of cytokines; activating other cells of the immune system T cells see these peptides when they are presented in MHC molecules. They do not respond to unbound antigen (unlike B cells – next lectures) T cells in action https://www.youtube.com/watch?v=jgJKaP0Sj5U, Gillian Griffiths lab, University of Cambridge CD8+ T effector CD4+ T effector cells cells Proportions found in the blood Cell type Percentage White Blood Cells (WBCs) 0.1-0.2% Lymphocytes (B cells and T 14 – 47% of WBCs cells) T cells 7 – 24% of WBCs CD4+ T cells 4 – 20% of lymphocytes CD8+ T healthy adults have about 1 8 In total, – 11% million of / ml of blood T cells lymphocytes Other types of T cells are found in smaller percentages Numbers are very different in other organs. For example, in the small intestine more than 75% of T cells are CD8+  Recognition of foreign cells by T cells T cells only recognise antigen through their T Cell Receptors (TCR) They cannot recognise antigen if it does not bind the TCR The TCR does not recognise antigen on its own, but only if bound within a Major Histocompatibility Complex molecule (MHC) These are important constraints on the activity of T cells; their function must be controlled as they can cause a lot of damage to host tissues T cell receptors can only recognise antigen in MHC MHC = Major Histocompatibility Complex This ‘restriction’ is essential to prevent autoimmunity MHC molecules bind to proteins from viruses and bacteria and present them to T cells They also bind to self peptides from the cell This is called Antigen Presentation The TCR interacts with MHC molecules to detect pathogens  Recognition of foreign cells by T cells The TCR allows T cells to recognise infected cells Heterodimer composed of α, β chains Each chain has two domains, one variable and one constant domain Recognition of foreign cells by T cells Complementarity Determining Regions (CDRs) - Where the TCR contacts the antigen There are three CDRs in the TCR variable domain T cell receptors are very diverse Salmonella Influenza  T cell receptors are very diverse Answer lies in VDJ recombination There are many genes that make up the TCR locus These genes rearrange to make many Combinational many receptors diversity: From the different combinations of gene segments Junctional diversity: From the addition of nucleotides when recombination occurs  The most variable regions are where the TCR meets the antigen – CDR3 This is due to junctional diversity – where extra nucleotides are added when the DNA segments join The other parts of the TCR are constant (useful for us) T cell receptors are very diverse Two types of MHC molecule Two types of MHC molecule Class I MHC Found on most nucleated cells Present endogenous antigens (intracellular, internal) Display self proteins, virus proteins, intracellular pathogens Present antigen to cytotoxic T cells (CD8) Class II MHC Found primarily on professional antigen presenting cells (APCs) Present exogenous antigens (extracellular, external) Phagocytosis, receptor mediated endocytosis Present antigen to helper T cells (CD4) Antigen presenting cells Three types of ‘professional’ APCs that express both MHC-I and MHC-II Dendritic cells macrophages B cells Cells other than APCs that express MHC-I are ‘target’ cells Target can be virus infected, malignant and aging cells, or cells from a graft Peptides bind in the MHC cleft MHC class I MHC class II Peptide ~8-10 aa Peptide ~13-25 aa  How do peptides get into MHC molecules? The peptides presented by MHC class I and class II molecules can be from: Self proteins Viral or bacterial proteins Exogenous proteins MHC genes are highly polymorphic The genes that code for MHC molecules have a lot of genetic diversity within a population Many different pathogenic peptides will be bound by MHC molecules Summary so far We need T cell responses for highly specific, precise attacks on pathogens that are not cleared by innate immunity In addition, T cells can provide long-lived memory responses which clear repeat infections quickly T cells develop in the thymus. Recombination means there is an enormous diversity of T cell receptors, meaning there can be recognition of a huge amount of peptide They can only recognize peptides bound in MHC molecules, on the surface of cells. T cell selection in the thymus 1. Expression of TCR = cells that can functionally signal and induce immunity 2. Positive selection = cells which can recognise MHC 3. Negative selection = cells which do not attack host antigen CD4+ or CD8+ cell Functional TCR Recognises MHC Does not respond to self-ag To get to this point 95% of T cells 27 die in the thymus Positive selection o CD4+ CD8+ cells live 3-4 days unless rescued by TCR engagement. Only small % of all generated TCRs will ever be able to functionally recognise MHC molecules – these are chosen to continue. Mouse thymus produces 50 million DP thymocytes per day. 5-10% survive positive selection o Want to find cells which recognise self-MHC weakly as these may recognise self-MHC + foreign- antigen strongly o Self-MHC presented by cortical thymic epithelial cells (cTECs) 28 o Cells which are rejected die by apoptosis o They are then taken up by resident macrophages Surh and Sprent (1994). Nature 372; 100-102 29 Positive selection 30 CD4 and CD8 o The positive selection of DP T cells also directs loss of CD4 or CD8 o If a new TCR recognises an antigen presented by MHC I, it loses CD4; if it recognises ag-MHC II, it loses CD8 o CD4 and CD8 are CO-RECEPTORS which also bind MHC and help TCR signalling o Bare lymphocyte syndrome – mutation in MHC II = no CD4 T cells; mutation in MHC I = no CD8 T cells 31 T cell selection in the thymus 1. Expression of TCR = cells that can functionally signal and induce immunity 2. Positive selection = cells which can recognise MHC 3. Negative selection = cells which do not attack host antigen CD4+ or CD8+ cell Functional TCR Recognises MHC Does not respond to self-ag To get to this point 95% of T cells 32 die in the thymus Negative selection o We need to have a way to reject cells which o recognise self MHC strongly o recognise self peptide - MHC strongly o As these cells are likely to react against self tissues and damage them 33 Negative selection 34  T cell maturation 1.Recognise self-MHC too strongly KILL 2.No self-MHC recognition KILL 3.Recognise self-peptide in self-MHC KILL 1 & 2 depend only on MHC expression 3 needs self antigen expression too 35 How can the thymus express antigens coded for by other organs and produced at different developmental stages? 36  The AIRE transcription factor Mark S. Anderson et al. Science 2002;298:1395-1401 37  Summary T cells recognise PEPTIDE antigens only if bound in the scaffold of an MHC molecule CD4 T cells are HELPER cells, CD8 T cells are CYTOTOXIC In the thymus positive and negative selection choose T cells which are Specific for an antigen which is NON self And which can only bind antigen in MHC And which do not react to self tissue