1. Major histocompatibility complex (MHC) and T cell receptors
Jennifer Nyland, PhD
Office: Bldg#1, Room B10
Phone:

2. Teaching objectives
To give an overview of role of MHC in immune response
To describe structure & function of MHC
To describe structure & function of TCR
To discuss the genetic basis for generation of diversity in TCR
To describe the nature of immunological synapse and requirements for T cell activation

3. Role of MHC in immune response
TCR recognizes Ag presented in MHC
Context is important
Binding of Ag peptides in non-covalent
Two types of MHC (class I and class II) are recognized by different subsets of T cells
CTL recognizes Ag peptide in MHC class I
T-helper recognizes Ag peptide in MHC class II

4. Structure of MHC class I
Two polypeptide chains
Long α chain and short β

5. Structure of MHC class I
Four regions
Cytoplasmic contains sites for phosphorylation and binding to cytoskeleton
Transmembrane contains hydrophobic AAs
Highly conserved α3 domain binds CD8
Highly polymorphic peptide binding region formed by α1 and α2

6. Structure of MHC class I Ag-binding groove
Groove composed of
α helix on 2 opposite walls
Eight β sheets as floor
Residues lining floor are most polymorphic
Groove binds peptides 8-10 AA long

7. Structure of MHC class I Ag-binding groove
Specific amino acids on peptide are required for “anchor site” in the groove
Many peptides can bind
Interactions at N and C-terminus are critical and “lock” peptide in grove
Center of peptide bulges out for presentation
Consideration in vaccine development

8. Structure of MHC class II
Two polypeptide chains
α and β
approx equal length

9. Structure of MHC class II
Four regions
Cytoplasmic contains sites for phosphorylation and binding to cytoskeleton
Transmembrane contains hydrophobic AAs
Highly conserved α2 and β2 domains binds CD4
Highly polymorphic peptide binding region formed by α1 and β1

10. Structure of MHC class II Ag-binding groove
Groove composed of
α helix on 2 opposite walls
Eight β sheets as floor
Both α1 and β1 make up groove
Residues lining floor are most polymorphic
Groove binds peptides AA long (some outside groove)

11. Important aspects of MHC
Individuals have a limited number of MHC alleles for each class
High polymorphism in MHC for a species
Alleles for MHC genes are co-dominant
Each MHC gene product is expressed on surface of individual cell

12. Important aspects of MHC
Each MHC has ONE peptide binding site
But each MHC can bind many different peptides
Only one at a time
Peptide binding is “degenerate”
MHC polymorphism is determined in germline
NO recombination mechanisms for creating diversity in MHC
Peptide must bind with individual’s MHC to induce immune response

13. Important aspects of MHC
How do peptides get into MHC groove?
Class I: peptides in cytosol associate with MHC
Class II: peptides from within vesicles associate with MHC
golgi ER
Class I
Cytoplasmic peptide
Class II
Ii chain
Peptide in vesicle
Displaces Ii chain

14. Important aspects of MHC
MHC molecules are membrane-bound
Recognition by Ts requires cell-cell contact
Mature Ts must have TCR that recognizes particular MHC
Cytokines (especially IFN-γ) increase expression of MHC

15. T cell receptor (TCR)

16. Role of TCR in immune response
Surface molecule on Ts
Recognize Ag presented in MHC context
Similar to Immunoglobulin
Two types of TCR
α β: predominant in lymphoid tissues
γ δ: enriched at mucosal surfaces

17. Structure of the TCR (αβ)
Heterodimer
α and β chains
approx equal length

18. Structure of the TCR (αβ)
Regions
Short cytoplasmic tail- cannot transduce activation signal
Transmembrane with hydrophobic AAs
Both α and β have a variable (V) and constant (C) region
V region is hypervariable, determines Ag specificity

19. Important aspects of TCR
Each T cell has TCR of only ONE specificity
Allelic exclusion
αβ TCR recognizes Ag only in the context of cell-cell interaction and in correct MHC context
γδ TCR recognizes Ag in MHC-independent manner
Response to certain viral and bacterial Ag

20. Genetic basis for receptor generation
Accomplished by recombination of V, D and J gene segments
TCR β chain genes have V, D, and J
TCR α chain genes have V and J

21. TCR and CD3 complex TCR is closely associated with CD3 complex
Group of 5 proteins
Commonly called “invariant” chains of TCR
Role of CD3 complex
CD3 necessary for cell surface expression of TCR
transduces signal after Ag interaction with TCR

22. The “immunological synapse”
TCR-MHC interaction is not strong
Accessory molecules stabilize interaction
CD4/MHC class II or CD8/MHC class I
CD2/LFA-3
LFA-1/ICAM-1

23. The “immunological synapse”
Specificity for Ag is solely in TCR
Accessory molecules are invariant
Cytokines change expression levels

24. The “immunological synapse”
Co-stimulation is also necessary for activation of T cells
CD28/CD80 or CD86
CTLA-4 on T cells can also ligate CD80/CD86
Inhibitory signal
downregulation

25. Key steps in T cell activation
APC must process and present peptides to Ts
Ts must receive co-stimulatory signal
Accessory adhesion molecules stabilize binding of TCR and MHC
Signal from cell surface is transmitted to nucleus
Cytokines produced help drive cell proliferation