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T Cell Receptor (TCR) & MHC Complexes-Antigen Presentation

T Cell Receptor (TCR) & 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

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T Cell Receptor (TCR) & MHC Complexes-Antigen Presentation

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

  3. Antibody, TCR & MHC

  4. Key Concepts in T-Cell Receptor (TCR)-I 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 peptides 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.

  5. Key Concepts in TCR-II 5. Like Ab (or BCR), TCR diversity is generated by VDJ recombination. 6. gd T cells function differently from ab T cells in MHC- independent manner.

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

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

  8. Murine T-cell Receptor (TCR) genes 1. Two types of TCR, ab and gd, serve distinct functions 2. VDJ recombination for TCR

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

  10. TCR & Accessory Molecules Accessory Molecules -Help T cells in response to a specific Ag 1. CD3 (e, g, d ) and 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. Interaction between innate and& adaptive immunity 1. Innate immunity => Ag presentation (by Dendritic cells) 2. Adaptive immunity => Ag recognition (by T & B lymphocytes)

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

  15. Interactions of Accessory molecules between T cells & APCs

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

  17. 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 extracellular (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)

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

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

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

  21. Schematic maps of human & mouse MHC loci

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

  23. 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.

  24. 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.

  25. 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 b1domain

  26. Allele-specific peptides from MHC molecules

  27. MHC genes are highly Polymorphic

  28. Expression of MHC alleles is co-dominant

  29. Polymorphism & Polygeny both contribute to the MHC diversity

  30. Polymorphism vs Polygeny of MHC 1. MHC molecules are polygenic. Every individual contains several different MHC-I & MHC-II genes with wide ranges of peptide-binding specificity. => Personal protection 2. MHC is highly polymorphic. Multiple variants of each MHC gene within the population function as a whole.

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

  32. Gene recombination creates new alleles in MHC genes

  33. MHC expression on cells-I

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

  35. 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”.

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

  37. 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, e.g. Cytokines & Surface Molecules

  38. Features of Ag recognition by T cells

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

  40. Functions of different APCs

  41. Features of different APCs

  42. 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.

  43. Overview of Dendritic cells in Ag capture & presentation

  44. MHC Restriction of cytotoxic T cells

  45. MHC Restriction-II

  46. For their work leading to the discoveries regarding the specificity of cell mediated immunity =>MHC-restriction for T cell recognition => Adaptive immunity

  47. Class I vs Class II MHC pathway

  48. The Class II MHC pathway of Ag Presentation

  49. The Class I MHC pathway of Ag Presentation

  50. Pathogen presentation by MHCs

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