T cell receptor & MHC complexes-Antigen presentation

1. T cell receptor & MHC complexes-Antigen presentation • Pin Ling (凌 斌), Ph.D. ext 5632; lingpin@mail.ncku.edu.tw • References: 1. Abbas, A, K. et.al, Cellular and Molecular Immunology (6th ed., 2007), Chapter 5-7 2. Male D., J. Brostoff, D. B Roth, and I. Roitt Immunology (7th ed., 2006), Chapter 5 & 7

2. Question What mechanisms to achieve the generation of Ab diversity? Ans: 1. VDJ gene recombination => V regions => Ag binding 2. Somatic hypermutation 3. Isotype switching => Fc portion => Effector function

3. Outline • Structures & Features of T-cell antigen receptor (TCR) • Structures & Features of Major Histocompatibility Complex (MHC) • Antigen presentation to T cells • Summary & Question

4. Antibody, TCR & MHC

5. Key Concepts in T-cell Receptor (TCR) 1. T-cell antigen receptor (TCR) is similar to the F(ab) of Ab but only located on the surface of T cells => No secreted form => Two major types: ab TCR and gd TCR 2. TCR functions to recognize Ag peptide and then to activate T cells => Adaptive immunity 3. Ag recognition by ab TCR requires Ag presented by Major Histocompatibility Complex (MHC). => consider both Ag peptide & MHC => Cell-Cell interaction 4. The Ag-binding site region of the TCR is formed by the Va and Vb regions.

6. Similarities & Differences between T-cell Receptor (TCR) and Ab

7. The Structure of T-cell Receptor (TCR)

8. T-cell Receptor (TCR) vs. Ab

9. Binding of a TCR to a peptide-MHC complex Side Front

10. TCR & Accessory Molecules Accessory Molecules -Help T cells in response to a specific Ag 1. CD3 (e, g, d & z chains): associates w/ TCR => intracellular signaling transduction 2. CD4/CD8: CD4  MHC-II CD8  MHC-I 3. CD28: a co-stimulatory receptor 4. Integrin: Adhesion & co-stimulation

11. The TCR/CD3 Complex TCR/CD3 Complex: 1. TCRab dimer + multiple CD3 dimers - CD3eg dimer - CD3ed dimer - CD3zz dimer 2. The ITAM motif on CD3 => Signaling Transduction

12. TCR/CD3 Complex vs BCR/Igab Complex

13. Interactions of Accessory molecules between T cells & APCs

14. Outline • Structures & Features of T-cell antigen receptor (TCR) • Structures & Features of Major Histocompatibility Complex (MHC) • Antigen presentation to T cells • Summary & Question

15. Key Concepts in Major Histocompatibility Complex (MHC) 1. Ag presentation to TCR is mediated by Two classes of MHC molecules. - Class-I MHC => peptides from cytosolic (intracellular) proteins => CD8 T cells - Class-II MHC => peptides from intracellular (exogenous) proteins from phagocytosis => CD4 T cells 2. In humans, the MHC is also called as the HLA (Human Leukocyte Antigen). 3. MHC genes are the most polymorphic genes present in the genome and co-dominantly expressed in each individual. 4. MHC molecules express on the cellular surfaces of only in presence of Ag-peptides. Class-I => all nucleated cells Class-II => APCs (DC, Macrophages & B cells)

16. TCR-Ag w/ Histocompatibility Complex (MHC)

17. The Discovery of Major Histocompatibility Complex (MHC) Histocompatibility genes: George Snell in 1940s => tumors or tissues => same strain, OK => foreign strains, No

18. For their work leading to the discoveries of MHC (mouse ) and HLA (human). - Immune recognition => The foundation of adaptive immunity - Transplantation

19. Schematic maps of human & mouse MHC loci

20. Class-I vs. Class-II MHC molecule

21. Structure of Class-I MHC molecule a1a2domains are polymorphic and form the peptide-binding cleft. a3domain is conserved among all MHC class-I, and folds into an Ig domain for CD8 binding.

22. Structure of Class-II MHC molecule a1b1domains are polymorphic and form the peptide-binding cleft. b2domain is conserved among all MHC class-II, and folds into an Ig domain for CD4 binding.

23. Polymorphic residues of MHC molecules In Class-I, polymorphic residues => the peptide-binding cleft formed bya1a2 domains In Class-II, polymorphic residues => the peptide-binding cleft formed bya1b1 domains In this case HLA-DR, polymorphism is on b1 domain

24. MHC genes are highly Polymorphic

25. Expression of MHC alleles is co-dominant

26. Polymorphism & Polygeny both contribute to the MHC diversity

27. Gene conversion creates new alleles in MHC genes => Copying sequences from one MHC gene to another

28. Gene recombination creates new alleles in MHC genes

29. MHC expression on cells-I

30. MHC expression on cells-II Expression of MHC molecules is increased by cytokines produced during innate & adaptive immune cells, ex. IFN

31. Features of Peptide-MHC interactions 1. MHC molecules show a broad spectrum for peptide binding, in contrast to the fine specificity of Ag recognition by Ab. 2. Peptide-MHC interactions are non-covalent and mediated by residues both in the peptides and in the clefts of MHC molecules. 3. Each MHC molecule binds one peptide at a time but can bind many different peptides. 4. MHC molecules do not discriminate between foreign peptides & self peptides.

32. Outline • Structures & Features of T-cell antigen receptor (TCR) • Structures & Features of Major Histocompatibility Complex (MHC) • Antigen presentation to T cells • Summary & Question

33. Key Concepts in Ag presentation between APCs & T cells 1. Most T cells recognize only peptides, whereas B cells can recognize peptides, lipids, nucleic acids,….etc. NK-T cells can recognize lipids. 2. T cells only recognize peptides displayed by MHC molecules on Ag-presenting cells (APCs). 3. APCs are responsible for capturing and displaying different Ags to T cells. 4. APCs serve two key functions for T cell activation: 1st function => process protein Ags to small peptides => form & present the peptide-MHC complex to T cells 2nd function => provide 2nd co-stimulatory signals, ex. Cytokines & surface molecules

34. Features of Ag recognition by T cells

35. T cells require APCs to respond to a specific Ag

36. MHC Restriction of cytotoxic T cells

37. Functions of different APCs

38. Features of different APCs

39. Dendritic cells –The Most effective APCs 1. Located at common sites of entry of microbes 2. Express receptors to capture microbes. 3. Migrate preferentially to T- cell zones in LNs. 4. Mature DCs express high levels of costimulators => T-cell activation.

40. Overview of Dendritic cells in Ag capture & presentation

41. Class I vs Class II MHC pathway

42. The Class II MHC pathway of Ag Presentation

43. The Class I MHC pathway of Ag Presentation

44. Ag Presentation to different T cell subsets

45. SUMMARY 1. TCR functions to recognize Ag peptides presented the MHC complexes => Ag peptide specificity => MHC restriction 2. Two classes of MHC molecules. - Class-I MHC => peptides from cytosolic (intracellular) proteins => CD8 T cells - Class-II MHC => peptides from intracellular (exogenous) proteins from phagocytosis => CD4 T cells 3. APCs serve two key functions for T cell activation: 1st function => process & present Ag peptides w/MHC to T cells 2nd function => provide 2nd co-stimulatory signals, ex. cytokines & surface molecules

46. Questions What is the Bare Lymphocyte Syndrome? What is the advantage of MHC Polymorphism? Is that good if MHC is as diverse as Ig or TCR?