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

2. T-cell receptor

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

6. TCR-CD3 complex

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

13. TCR-MHC interaction

14. T cell functions

15. Structure of MHC

16. TCR-MHC interaction

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

41. MHC restriction

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