copyright © 2005 by garland science publishing antigen recognition by t lymphocytes
TRANSCRIPT
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Copyright © 2005 by Garland Science Publishing
Antigen Recognition by T Lymphocytes
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T-cell receptor
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Organization and rearrangement of the TCR genes
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T cell development
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SCID : severe combined immunodeficiency disease
RAG1/2 mutant in Ig and TCR gene rearrangementDefect in T and B cell development
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TCR-CD3 complex
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-TCR and -TCR
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Antigen processing and presentation
Antigen Presenting Cell (APC); virus infected cell, tumor, phagocytes Ag processing: digestion of antigen Ag presentation: peptide on MHC molecule required for T cell activation
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Co-receptor : CD4 vs. CD8
TCR recognizes antigen through MHCMHC class I - all nucleated cells MHC class II - dendritic cells, macrophages, B cellsCD4 - helper T cell (Th) CD8 - cytotoxic T cell (Tc); alpha & beta
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TCR-MHC interaction
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T cell functions
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Structure of MHC
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TCR-MHC interaction
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Peptide-binding groove of MHC molecules
MHC Class I: somewhat closed endMHC Class II: somewhat open end - accommodate longer peptides
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MHC-Peptide interaction
Degenerate binding specificity Class I : 8-10 a.a hydrophobic or basic residue at C terminus Class II : 13-25 a.a
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Conformation of peptides bound to class I MHC
Different length - arch
TCR
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The vesicular system
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• MHC Class I: intracellular antigens, e.g. viral proteins produced in virus-infected cells; peptide degradation in cytosol by proteasome, then transport to ER
• MHC Class II: extracellular antigens, e.g. pathogen engulfed by phagocytes; degradation in phagosome and lysosome
Peptide loading on MHC
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Peptide transport into the ER
Proteasome: protease complex used to break down proteins that are damaged, poorly folded or no longer neededTAP : transporter associated with antigen processing ATP-dependent transport
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Assembly and peptide loading of class I MHC
Molecular Chaperone
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ERAP (endoplasmic reticulum aminopeptidase):
removes amino acids from N-terminus
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• Bare lymphocyte syndrome: non-functional TAP - no MHC Class I on cell surface (due to lack of peptide on MHC)
• Autoimmunity: in normal state, MHC class I presents self peptide, which causes no reaction (due to negative selection during thymocyte development); however, in some cases, self-reactive T cells survive and cause autoimmunity
MHC Class I-related diseases
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Peptide binding of class II MHC
• invariant chain: blocks binding of peptides in ER• CLIP : class II-associated invariant-chain peptide• HLA-DM causes displacement of CLIP, and then allows loading of peptide onto MHC
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Ag processing and presentation
• Class I MHC ; endogenously synthesized proteins, cytosolic degradation
• Class II MHC ; exogenous antigens, endocytic degradation
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TCR-Peptide –MHC complex
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Antigen presenting cells
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Major histocompatibility complex (MHC)
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• allele: two or more alternative forms of a gene at a particular locus
• haplotype: the set of alleles of linked genes present on one parental chromosome
• polymorphic
• heterozygous, homozygous
• syngenic: strains with all identical genetic loci
• congenic: strains with all but a single genetic locus
• autologous : self-MHC isoform
• allogeneic: all other MHC isoform
• alloreactive: reactive against any given allogeneic cell;
e.g. potent T cell response that attacks the graft
Glossary
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Human MHC isotypes
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Haplotypes
Allelic forms of MHC genes ; polymorphic, co-dominant
Inbred strain ; homozygous, identical haplotype
Prototype
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Various MHC molecules expressed on APCs (H-2k/d)
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Variation between MHC allotypes
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MHC restriction
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NK cells target cells for killing that have aberrant MHC expression– Distinguish healthy cells from infected cells or tumors
NK cell receptor
Opposing-signals model ;
Activation signals :AR
Inhibitory signals; IRS
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NK cell alloreaction
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