Copyright © 2005 by Garland Science Publishing

Antigen Recognition by T Lymphocytes

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 rearrangementDefect in T and B cell development

TCR-CD3 complex

-TCR and -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 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

TCR-MHC interaction

T cell functions

Structure of MHC

TCR-MHC interaction

Peptide-binding groove of MHC molecules

MHC Class I: somewhat closed endMHC 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

Conformation of peptides bound to class I MHC

Different length - arch

TCR

The vesicular system

• 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

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

Assembly and peptide loading of class I MHC

Molecular Chaperone

ERAP (endoplasmic reticulum aminopeptidase):

removes amino acids from N-terminus

• 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

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)

• 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

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 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

NK cell alloreaction