Talk 5

1. Talk 5 T细胞受体与主要组织相容性 复合体分子 T-Cell Receptor and Major Histocompatibility Complex Molecules

2. Overview • T cells recognize antigens that are presented by antigen presenting cells (APCs) only • The way which TCR recognizes antigens is quite different from antigen recognition by antibody (e.g. recognize antigen fragments presented by MHC molecules only) • The most important antigen-presenting molecules are class I and class II molecules of MHC, and more recently other antigen-presenting molecules have been identified (e.g. CD1 presents lipid and glycolipid antigens) • However, antibody and TCR have many similarities, they are structurally related (folded into Ig superfamily domains), clonally distributed (each has a receptor with individual specificity) and their receptors are generated by somatic recombination (体细胞重组) from a limited number of germ line (生殖系) genes

3. The  TCR heterodimer forms the recognition unit of the receptor The CD3 complex associates with the  or γδforms of TCR The γδTCR structurally resemble the TCR The external portion of each chain consists of two domains, resembling Ig variable and constant domains TCR:CD3 Complex

4. The organization of the gene segments for TCR  and  chains is generally homologous to the L chain and H chain of Ig gene segments, respectively Like Ig genes in B cells, TCR gene segments rearrange during development to form complete V-domain exons The process takes place in the thymus TCR serves only for antigen recognition and its constant region genes are much simpler TCR Gene and Expression

5. Number and Diversity between TCR and Ig Gene Segments TCR diversity is focused in CDR3. Somatic hypermutation is not a major mechanism for generating diversity in TCR

6. Major Histocompatibility Complex Molecules • The gene complex was first identified based on the ability of a donor to accept grafts from the recipient sharing the same MHC hapotype • MHC contains >100 gene loci, but only class I and class II molecules determine graft rejection and present antigens • MHC class I and II molecules are highly polymorphic cell-surface glycoproteins • The gene complex in mouse is called H-2 and in human leukocyte antigen (HLA) system • The remaining genes in MHC are very diverse, including genes coding for complement components (C4, C2 and factor B), cytokines, enzymes, heat-shock proteins and other molecules involved n antigen processing, which are collectively called class III genes

7. Overall Organization of MHC • Three human class I loci, two or three mouse class I loci; • Human class II genes are located in the HLA-D region, while murine class II genes are located in the H-2I region

8. MHC Class I Molecules • Consist of an MHC-encoded heavy chain bound toβ2-microglobulin • β2-microglobulin is essential for expression of MHC class I molecules • Heavy chain α1 and α2 domains form the antigen-binding groove • Variations in amino acid sequence change the shape of the binding groove

9. MHC Class II Molecules The overall structure resembles class I molecules

10. Interactions of MHC Molecules with Antigenic Peptides • T cells recognize the appropriate MHC molecule bound-peptides only • In a MHC class I molecule, the bound peptide is surrounded by the two  helices from 1 and 2 domains • In a MHC class II molecule, the peptide is held between the  helices of the 1 and 1 domains

11. Interactions of MHC Molecules with Antigenic Peptides • MHC class II binding groove accommodates longer peptides than class I • Peptides are held in the binding cleft by characteristic anchor residues

12. The length of Peptides Bound by MHC Class II Molecules • The peptide lies in an extended conformation along the peptide-binding groove • In principle, no upper limit on the length of peptides binding to the molecules, but longer peptides are trimmed by peptidases to 13-17 amino acids in most cases • Amino acid side chains at residues 1, 4, 6, and 9 of a minimal MHC class II-bound peptide are held in the binding pockets It is more difficult to detect a peptide-binding motif for MHC class II molecules

13. MHC Polymorphism Affects Antigen Recognition • Individual MHC molecules can differ by up to 20 amino acids • Most of the differences are on the surfaces of the outer domain, the peptide-binding groove in particular • Different allelic variants of MHC molecules bind different peptides • Previously called immune response (Ir) gene encodes MHC class II molecules • Polymorphism of MHC molecules guarantees sufficient MHC molecules to avoid non-responsiveness

14. Distribution of MHC Molecules • Different distribution of MHC molecules reflects the functions of T cells • Class I molecules present intracellular antigenic peptides to CD8+Tc cells，inducing cellular immune response (CTL) • The main function of CD4+ T cells is to activate other effecter cells and thus MHC class II molecules are present mainly on APC • The expression levels of MHC molecule influence activation of T cells

15. Aggregation of TCRs initiates T-cell activation Antigenic peptides can induce or antagonize T-cell activation CD4 and CD8 are co-receptors of TCR APC MHC I/II CD8/4 TCR T Interaction of TCR with MHC-Bound Antigens

16. A T cell specific for MHCa-peptidex will not recognize MHCb-peptidex or MHCa-antigeny Co-recognition of peptide and MHC molecule is known as MHC restriction (the MHC molecules restrict the ability of the T cell to recognize antigen) The restriction may result from direct contact between MHC molecule and TCR or indirect effect of MHC polymorphism on the peptides MHC Restriction