1. T Cell Receptor (TCR) & MHC Complexes-Antigen Presentation
Pin Ling (凌 斌), Ph.D.
ext 5632;
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 are the mechanisms to generate 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
-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. Interactions of Accessory molecules between T cells & APCs

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

16. 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)

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

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

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

20. Schematic maps of human & mouse MHC loci

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

22. Structure of Class-I MHC molecule
a1a2 domains are
polymorphic and form the peptide-binding cleft.
a3 domain is conserved among all MHC class-I, and folds into an Ig domain for CD8 binding.

23. Structure of Class-II MHC molecule
a1b1 domains are
polymorphic and form the peptide-binding cleft.
b2 domain is conserved among all MHC class-II, and folds into an Ig domain for CD4 binding.

24. Polymorphic residues of MHC molecules
In Class-I, polymorphic
residues => the
peptide-binding cleft
formed by a1a2 domains
In Class-II, polymorphic
formed by a1b1 domains
In this case HLA-DR,
polymorphism is on b1domain

25. MHC genes are highly Polymorphic

26. Expression of MHC alleles is co-dominant

27. Polymorphism & Polygeny both contribute to the MHC diversity

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

29. Gene recombination creates new alleles in MHC genes

30. MHC expression on cells-I

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

32. 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”.

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

34. 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

35. Features of Ag recognition by T cells

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

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. MHC Restriction of cytotoxic T cells

42. MHC Restriction-II

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

44. Class I vs Class II MHC pathway

45. The Class II MHC pathway of Ag Presentation

46. The Class I MHC pathway of Ag Presentation

47. Pathogen presentation by MHCs

48. Ag Presentation to different T cell subsets

49. SUMMARY 1. TCR functions to recognize Ag peptides presented by
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 extracellular (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

50. 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?