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Recognition of Antigen By T cells: The TCR March 23, 2009 11:00-12:00 THE POLYPEPTIDES OF THE TCR TCR is a heterodimer a and b chains are 40-50 kD glycoproteins Both chains have V and C regions The ab TCR is on most T cells There is a second TCR that contains gd TCRs T cells with the gd TCR are in the gut and skin. Job description remains to be determined. THE TCR IS A MEMBER OF THE Ig SUPERFAMILY Both V and C regions form domains like those in Ig TCR V regions are similar in size to Ig V regions TCR POLYPEPTIDE GENES ARE ON TWO LOCI The b locus has the most V genes The g and d loci have the fewest V genes Although both b and g have two C regions, there is no isotype switching Not all loci have both D and J segments TCR V REGIONS ARE FORMED FROM MULTIPLE GENE SEGMENTS TCR gene rearrangement uses the same machinery as Ig genes FUNCTIONAL REGIONS OF TCR POLYPEPTIDES Each V region has 3 CDRs C regions have 4 domains extracellular hinge transmembrane cytoplasmic SHORT CYTOPLASMIC TAIL= NO SIGNAL TRANSDUCTION TCR GENERATION OF DIVERSITY IS SIMILAR TO Ig 1. Multiple V 2. Combinations of gene segments 3. Junctional diversity: TCR>>>Ig 4. Pairing of a and b or g and d TCR EXPRESSION REQUIRES ASSOCIATION WITH OTHER PROTEINS TCR on T cells is associated with the CD3 complex and a non-CD3 dimer The TCR (like Ig) is responsible for antigen recognition The other proteins (like Iga and Igb) are responsible for signal transduction The CD3 Proteins (g,d,e) Highly homologous All of them are on chromosome 11 All of them can be divided into 4 regions 1. N-terminal extracellular Ig domain 2. Short connecting peptide 3. Transmembrane region containing negatively charged amino acids 4. Cytoplasmic tail CYTOPLASMIC TAILS OF CD3 PROTEINS ARE RESPONSIBLE FOR SIGNAL TRANSDUCTION ITAMS: Immunoreceptor tyrosine based activation motif Motif important for signal transduction Present in cytoplasmic tails of other proteins involved in signaling The non-CD3 signaling proteins: z and h Both proteins come from a single gene Most TCR complexes contain zz homodimers Some TCR complexes contain zh heterodimers Cytoplasmic tails have ITAMs TCR AND BCR (mIg) RECOGNIZE ANTIGEN DIFFERENTLY Binding Sites: BCR has multiple sites TCR has a single site What they recognize: BCR recognizes “free”, intact antigen TCR recognizes processed antigen presented in the context of MHC ANTIGEN PROCESSING AND PRESENTATION ANTIGEN PROCESSING is the intracellular generation of peptides from protein ANTIGEN PRESENTATION is the association of those peptides with MHC on the cell membrane MHC CLASS I A single a chain with three domains It is associated with a second protein, b2 microglobulin MHC CLASS II MHC class II is an ab heterodimer Each chain has a peptide binding site associated with an Ig-like domain TWO CLASSES OF T CELL Classes of T cell are defined by expression of CD4 and CD8 glycoproteins CD8 cells are cytotoxic CD4 T cells are helpers CD4 and CD8 determine MHC class binding CO-RECEPTOR ASSOCIATION WITH MHC MHC class I binds CD8 MHC class II binds CD4