Lecture5.pptx

Immunology BE433 Dr Christine Loscher Lecture 5 Antigen recognition by T cells Antigen presentation to T cells Development of T cells • Lymphocytes orginate in bone marrow • T cells develop in the thymus from precursor cells that migrate from the bone marrow • Antigen specificity of a lymphocyte i...

Immunology BE433 Dr Christine Loscher Lecture 5 Antigen recognition by T cells Antigen presentation to T cells Development of T cells • Lymphocytes orginate in bone marrow • T cells develop in the thymus from precursor cells that migrate from the bone marrow • Antigen specificity of a lymphocyte is determined early on in its differentiation when the DNA sequences encoding the variable regions of the TCR are assembled from gene segments • TCR tested for its antigen-recognition properties against molecules in immediate environment • Their specificity determines their fate – positive and negative selection Figure 7-2 Movie How do T cells see antigen? • Antigen recognition molecules of T cells are membrane proteins – T cell receptor (TCR) • Its only function is to signal T cells for activation • Does NOT recognise and bind antigen directly • Recognises short peptide fragments of pathogen’s protein antigens which are bound to Major Histocompatability Complex (MHC) molecules on the surface of other cells – distinctive feature of T cells • T cells can recognise intracellular pathogens, viruses and pathogen products that cells have internalised T cell receptor (TCR) • TCR closely related to antibody molecules • Each T cell bears approx 30,000 identical antigenreceptor molecules on its surface • Receptor consists of α and β polypeptide chains linked by a disulphide bond • α:β heterodimer similar in structure to Fab fragment of Ab – (γδ alternative) • TCR only has one binding site • Never secreted Figure 3-11 Figure 3-12 TCR contd…. • Amino terminal variable (V) region • A constant (C) region • Short hinge region containing a cysteine residue that forms the disulphide link between the 2 chains • Hydrophobic transmembrane domain • Differences between TCR and Fab in the C region • Interaction between V and C regions different TCR recognises antigen in the form of peptide bound to MHC • Very different from how B cells can recognise intact antigens • T cells respond to short amino acid sequences of proteins • These sequences are often buried within the naïve protein and so are only recognised by TCR after unfolding of the protein and processing of it into peptide fragments • The ligand recognised by the TCR is a complex of peptide and MHC molecule CD4 and CD8 T cells • 2 classes of T cell with different effector functions • Distinguished by the expression of cell surface proteins CD4, CD8 • CD8 – MHC 1 • CD4 – MHC 2 • During antigen recognition CD4/8 associate on the cell surface with the TCR and bind to sites on the MHC molecule – this is necessary for effective response • CD4, CD8 are co-receptors Figure 3-15 CD4 and CD8 • Binds a site on the MHC2 that is well away from where the TCR binds it – therefore CD4/8 and TCR bind the same peptide:MHC complex • CD4/8 interacts strongly with an thyrosine kinase in the cytoplasm (Lck) and can deliver this kinase close to the signaling components of the TCR complex – this results in enhancement of the signal generated from the TCR binding the peptide:MHC complex • Increases the sensitivity of the cell to antigen presented by MHC • CD4/8 binding alone to MHC is weak – no signal MHC • MHC1 and 2 are distributed differently on cells • MHC1 present peptides from pathogens, commonly virus to CD8 cytotoxic T cells – specialised to kill any cell they recognise • As virus infect also any nucleated cell, almost all these cells express MHC1 but at different levels • Non-nucleated cells – red blood cells – express little or no MHC1 – interior of red blood cells is a site that can go undetected by cytotoxic T cells • Consequences for plasmodium species – causes malaris to live undetected in bed blood cells MHC contd…… • CD4 T cells recognise MHC2 and activate other effector cells of the immune system • MHC2 found on dendritic cells, B cells and macrophages but not other tissue cells • When CD4 T cells recognise peptides bound to MHC2 on B cells they stimulate Ab production • When they recognise peptides bound to MHC2 on macrophages they activate them to destroy pathogens in their vesicles • Expression of MHC1 and 2 is regulated by cytokines released in the immune response – particularly Interferons Figure 3-19 part 1 of 2 Figure 3-19 part 2 of 2 MHC contd…. • Numerous different pathogens – will not generally have similarites in their peptide sequences • If T cells are to be alerted to all possible infections the MHC molecules must be capable of binding stably to many different peptides • Distinct from other peptide binding receptors – usually bind only one • MHC are unstable when not bound – the bound peptide is an integral part of the MHC molecules structure • Stability of bound peptides very important – peptide exchanges at the cell surface Summary • TCR recognise peptides bound to MHC on the surface of another cell – antigen presenting cell • CD8 cytotoxic T cells– MHC1 • CD4 helper T cells – MHC2