1. MHC: The antigen-presenting receptors

2. The key role of MHC molecules in presenting antigens to antigen-sensitive cells 0 The Major Histocompatibility Complex MHC restriction Antigen-presenting cell (M  , LB, dendritic cell) MHC Epitope: Ag fragment Ag receptor Antigen-sensitive cell (T cell CD4, CD8)

3. CLASS I CLASS II CLASS III Receptors for endogenous Ag (nucleted cells) Not found on gametes, neurons. Receptors for exogenous Ag (APC) A mixed group of proteins (including C´components) The three major classes of genes within the MHC chromosome The Major Histocompatibility Complex

4. COMPARISON OF MHC CLASS I AND MHC CLASS II MOLECULES CLASS Ia CLASS II Loci A, B and C DP,DQ, DR, DO and DN Method of detection Serology Serology and mixed lymphocyte reaction Distribution Nucleated cells B cells, macrophages and dendritic cells Function Present Ag to citotoxic T cells (CD 8) Present Ag to helper T cells (CD4) Result Citotoxicity Cooperation

6. Peter C. Doherty, DVM. Australia St. Jude Children's Research Hospital Memphis, TN, USA b. 1940 Rolf M. Zinkernagel Switzerland University of Zurich, Institute of Experimental Immunology Zurich, Switzerland b. 1944 1996, Nobel Prize for Medicine

8. Transmembrane  1  2  3  2m Citoplasmic A three-dimensional representation of a class I MHC molecule on a cell membrane  alpha  2m beta 2 microglulin MHC Class I Nucleated cells Ig domain Binding site to T cells Peptide-binding groove

9.  2-micro-globulin MHC Class I Lateral view  1  2  3  1  2 Peptide Top view

10.  1  1  2 Transmembrane Citoplasmic The overall structure of an MHC class II molecule MHC Class II Antigen-presenting cells  1 Ig domain Binding site to T cells Peptide-binding groove  2 

11. MHC class II molecule  Peptide  1  2  Cleft is made of both  and  chains   1

12. Cleft geometry MHC class I accommodate peptides of 8-10 amino acids  -M  -chain Peptide MHC class II accommodate peptides of >13 amino acids  -chain  -chain Peptide

13. MHC I MHC II

16. Endogenous peptides Exogenous peptides Citotoxicity Humoral response Cellular response  1  2  3  2m  1  1  2  Tc CD 8 Th CD 4

17. ACCEPTED Inbred mouse strains - all genes are identical Transplantation of skin between strains shows that rejection or acceptance is dependent upon the genetics of each strain REJECTED Genetic basis of transplant rejection Skin from an inbred mouse grafted onto the same strain of mouse Skin from an inbred mouse grafted onto a different strain of mouse

19. Transplant rejection is due to an antigen-specific immune response with immunological memory. Immunological basis of graft rejection Primary rejection of strain skin e.g. 10 days Secondary rejection of strain skin e.g. 3 days Primary rejection of strain skin e.g. 10 days CD8 Transfer lymphocytes from primed mouse 6 months

20. … And the MHC Class III?... CLASS I CLASS II CLASS III Receptors for endogenous Ag (nucleated cells) Receptors for exogenous Ag (APC) A mixed group of proteins The three major classes of genes within the MHC chromosome C4, C2, B, TNF-  and  , Heat shock protein 70 (HSP 70)

21. Production site Function The overall arrangement of genes within the mouse MHC class III region MHC Class III C4 C2 B 21-OH TNF  TNF  HSP Liver M  Adrenal M  Many cells Host defenses Steroid breakdown Tumor cell destruction Protection Vs damage

22. Father Mother Father Mother

24. The optimal number of MHC molecules 2 4 6 8 10 12 Number of MHC genes Susceptibility to infection Risk of autoimmunity.

25. Regulation of Immune Response by MHC. MHC Restriction

27. MHC molecules act to regulate the immune response Immune response No immune response Antigen MHC gene B APC CD4 MHC class II MHC gene A APC CD4