2. The Major Histocompatibility Complex (MHC)
January 31, 2018
Pete Burrows
What it is
What it does
Required for antigen recognition by T lymphocytes

3. Preview of antigen processing/presentation
Discovery and function of MHC
MHC structure
The similarities and differences between MHC class I and class II expression and function
The consequences of MHC polymorphisms
NKT cells

4. Antigen-antibody Interaction
Heavy Chain
Lysozyme
Antigenic Determinant
Epitope
Light Chain

5. Antigen must be “processed” inside of cells and then displayed
on the cell surface
to be recognized
by T cells
Proteases
TCR #1
TCR #2
Protein either taken up from the outside or produced intracellularly. In this case a foreign peptide, taken up by phago- or pinocytosis. TCR can recognize peptide but not by itself. Needs to be associated with self MHC.
Lysozyme

6. T cells recognize processed (degraded) protein antigens plus MHC
from lysozyme
TCR 2

7. Phagocytosis Processing of external antigens
MHC always has a peptide, usually from self
This is a foreign peptide that will alert the T cells of the immune system. Dendritic cells even better at this APC function than macrophages.
Processing of external
antigens
Complex is recognized by T helper cells
Dendritic cells are even more potent APC

8. Processing of internal antigens
Death Signal!
Viral protein
Foreign
Proteasome
Stay tuned for Dr. Collawn’s lecture about how this happens

9. Major Histocompatibility Complex
Discovered using inbred strains of mice and examining tumor immunity

10. Major Histocompatibility Complex - MHC
Discovered using inbred strains of mice and examining tumor immunity
Were really studying transplantation immunology – histocompatibility antigens
MHC is the major histocompatibility antigen that needs to be matched for organ transplantation
A complex of linked genes encodes the MHC proteins
Normal function of MHC is to display peptide antigens (self AND non-self) to T cells

11. MHC MHC I and MHC II MHC and T cell responses Expression and function
Structure
Genes and polymorphisms
MHC and T cell responses

12. MHC Class I Protein expressed on all nucleated cells
Presents peptide to CD8 T cells
Cytotoxic “killer” cells
Kill virus infected cells
Virus infected cell
All cells can potentially be infected by viruses
Tc killing virus infected cells

13. MHC Class II Expressed by specialized antigen presenting cells (APC)
Dendritic cells
B cells
Macrophages
Presents peptide to CD4 T cells
“Helper” T cells
Help B cells proliferate, differentiate, isotype switch
Help activate macrophages to kill intracellular pathogens
DC polarized Th response,Th1 h2, Th17, etc.

14. CD4 T cell helping a B cell

15. B Cell #1 Class I Class II Self peptide Foreign protein/peptide BCR
The fact that the Th and the B cell are recognizing the same antigen is sometimes a little unclear mechanistically.
Self peptide
Foreign protein/peptide
BCR

16. B B Cell Cell #1 #2 CD4 T Cell TCR Class I Class II Self peptide
Immune surveillance. T cell has to have a TCR specific for this particular peptide-MHC. Lots of other cells doing surveillance that will ignore this because TCR not specific for this.
Class I
Class II
Self peptide
Foreign peptide
CD4
T Cell

18. Class I and Class II MHC Molecules
Membrane bound glycoproteins
Structurally very similar
Both have 4 domains
2 membrane proximal domains
2 membrane distal domains that form a peptide binding cleft

19. MHC Structure
Class II
Class I

20. 3-D Structure of Human Class I HLA Molecule

21. Peptide
T cell view

22. The human MHC gene complex HLA – human leukocyte antigen
No gene rearrangements in MHC!
Classical MHC molecules. No allelic exclusion, so both chromosome genes expressed.

23. Expanded view of the human MHC
Class III includes complement components like C2, C4 and Factor B.

24. MHC Polymorphisms Allelic variations in MHC genes
Concentrated in the peptide binding regions of Class I and Class II

25. The human MHC gene complex HLA – human leukocyte antigen

26. MHC Polymorphisms

27. MHC Polymorphisms Allelic variations in MHC genes
Concentrated in the peptide binding regions of Class I and Class II
Population level
In an individual, all parental HLA-DP are identical, all maternal HLA-B, are identical, etc.

29. Consequences of MHC Polymorphism
Organ and tissue transplants are difficult
Polymorphic residues change the peptide binding specificity of the MHC
If all MHC were identical, pathogens might avoid immune detection by mutation to prevent MHC binding
Can do transplants not because of better MHC matching but potent immunosuppressive drugs. If no MHC-viral peptide, the virus infected cell becomes invisible to adaptive T cell response. No killing.

30. NKT cells
A subset of T cells that express an αβ T-cell receptor, but also express a variety of molecular markers that are typically associated with NK cells, such as NK1.1. 
Unlike NK cells, NKT cells express ab TCR and undergo TCR gene rearrangement in the thymus
Conventional T cells recognize peptide MHC
NKT cells recognize lipid and glycolipid antigens in association with CD1d, an MHC class I-like molecule
⍺-galactosylceramide (αGalCer) is an exogenous NKT cell ligand that can be used to activate NKT cells in vitro and in vivo.
Unlike NK cells, NKT cells express ab TCR. Most commonly used mouse strains (apart from C57BL/6) do not express the NK1.1 marker NKT cells arise in the thymus from a common precursor pool of CD4+CD8+ double-positive thymocytes that have undergone random TCR gene rearrangement and expression. Expression of a TCR that binds with appropriate avidity to MHC class II or I (MHCII or MHCI; plus self-peptide) on thymic epithelial cells leads to the positive selection of conventional CD4+ T cells (green) or CD8+ T cells (blue), respectively. Thymocytes that express a TCR that binds to CD1d plus self-lipid or glycolipid antigen, expressed by other double-positive thymocytes, enter the NKT cell lineage (red). Once selected, NKT cell precursors undergo a series of differentiation steps that ultimately results in the NKT cell pool. At least four distinct NKT cell development stages have been defined through differences in expression of CD24, CD44 and NK1.1;

31. NKT cells
Develop normally in MHC KO mice but not in β2-macroglobulin KO mice
Have an “invariant” TCR: Vα14-Jα18: Vβ8.2, 7, 2 (mouse) Vα24-Jα18: Vβ11 (human)
Jα18 KO mice lack NKT cells
TCRβ
TCR

32. NKT cell functions
NKT cells are able to produce large quantities of cytokines within minutes to hours of antigenic stimulation
Many proposed functions
“Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells. Gaya, et al. Cell 172:517 (2018)
NKT cells are the initial source of IL-4 needed for B cell proliferation, isotype switching etc.