Antigen Recognition by T Lymphocytes Copyright © 2005 by Garland Science Publishing

T-cell receptor

Organization and rearrangement of the TCR genes

T cell development

SCID : severe combined immunodeficiency disease RAG1/2 mutant in Ig and TCR gene rearrangement Defect in T and B cell development

TCR-CD3 complex

ab-TCR and gd-TCR

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

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

TCR-MHC interaction

T cell functions

Structure of MHC

TCR-MHC interaction

Peptide-binding groove of MHC molecules MHC Class I: somewhat closed end MHC Class II: somewhat open end - accommodate longer peptides

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

TCR Conformation of peptides bound to class I MHC Different length - arch

The vesicular system

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

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

Assembly and peptide loading of class I MHC Molecular Chaperone

ERAP (endoplasmic reticulum aminopeptidase): removes amino acids from N-terminus

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

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

Ag processing and presentation Class I MHC ; endogenously synthesized proteins, cytosolic degradation Class II MHC ; exogenous antigens, endocytic degradation

TCR-Peptide –MHC complex

Antigen presenting cells

Major histocompatibility complex (MHC)

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

Human MHC isotypes

Haplotypes Allelic forms of MHC genes ; polymorphic, co-dominant Inbred strain ; homozygous, identical haplotype Prototype

Various MHC molecules expressed on APCs (H-2k/d)

Variation between MHC allotypes

MHC restriction

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

NK cell alloreaction