1 Antigen Recognition by T Lymphocytes
Copyright © 2005 by Garland Science Publishing
3 Organization and rearrangement of the TCR genes
4 T cell development
5 SCID : severe combined immunodeficiency disease
RAG1/2 mutant in Ig and TCR gene rearrangement Defect in T and B cell development
7 ab-TCR and gd-TCR
11 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
12 Co-receptor : CD4 vs. CD8 TCR recognizes antigen through MHC
MHC class I - all nucleated cells MHC class II - dendritic cells, macrophages, B cells CD4 - helper T cell (Th) CD8 - cytotoxic T cell (Tc); alpha & beta
14 T cell functions
15 Structure of MHC
18 Peptide-binding groove of MHC molecules
MHC Class I: somewhat closed end MHC Class II: somewhat open end - accommodate longer peptides
19 MHC-Peptide interaction
Degenerate binding specificity Class I : 8-10 a.a hydrophobic or basic residue at C terminus Class II : a.a
20 TCR Conformation of peptides bound to class I MHC Different length - arch
21 The vesicular system
22 Peptide loading on MHC 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
24 Peptide transport into the ER
Proteasome: protease complex used to break down proteins that are damaged, poorly folded or no longer needed TAP : transporter associated with antigen processing ATP-dependent transport
25 Assembly and peptide loading of class I MHC
Molecular Chaperone
26 ERAP (endoplasmic reticulum aminopeptidase):
removes amino acids from N-terminus
27 MHC Class I-related diseases
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
28 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
30 Ag processing and presentation
Class I MHC ; endogenously synthesized proteins, cytosolic degradation Class II MHC ; exogenous antigens, endocytic degradation
31 TCR-Peptide –MHC complex
32 Antigen presenting cells
33 Major histocompatibility complex (MHC)
34 Glossary 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
35 Human MHC isotypes
36 Haplotypes Allelic forms of MHC genes ; polymorphic, co-dominant
Inbred strain ; homozygous, identical haplotype Prototype
37 Various MHC molecules expressed on APCs (H-2k/d)
40 Variation between MHC allotypes
42 NK cell receptor Opposing-signals model ; Activation signals :AR
Inhibitory signals; IRS NK cells target cells for killing that have aberrant MHC expression Distinguish healthy cells from infected cells or tumors
43 NK cell alloreaction