Transcript Antigen recognition by T Lymphocytes

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
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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