MHC Restriction and IR genes

1. MHC Restriction and IR genes January 15, 2007

2. 1-1. McDevitt, H.O. and Chinitz, A. Genetic control of the antibody response: Relationship between immune response and histocompatibility (H-2) type. Science 163:1207-1208. (1969).

3. Sandylop Himalayan It all began with some rabbits

4. and some antigens Synthetic polypeptide antigens -branched multichain synthetic polypeptides -not defined structures -(T,G)-A-L; (H,G)-A-L; (P,G)-A-L R=poly (tyrosine,glutamine acid =poly (histidine,glutamic acid) =poly (proline,glutamic acid) R R R Poly-D,L -alanine Poly-L -lysine R R Michael Sela-Weissman Institute for Sciences, Rehovot, Israel

5. People and Places • John Humphrey-Mill Hill, UK • Early pioneer in modern immunology with wide interests • Brigette(Ita) Askonas-Mill Hill, UK • Emil’s postdoctoral advisor • Don Shreffler-Wash U-Genetics • H-2 Immunogeneticist • Jan Klein-US/Germany/US • Immunogeneticist, prolific author, iconoclast

6. Sandylop: (Mill Hill) Non-responder to (T,G)-A-L Himalayan: (Israel) Responder to (T,G)-A-L It all began with some rabbits

7. MHC Congenic Mouse Strains 1948- George Snell (The Jackson Laboratory) • Using skin transplantation he examined what he termed “histocompatibility genes” = H genes • The H gene for antigen II was designated H2, later changed to H-2 • He realized that the first step in the genetic analysis of histocompatibility was the separation and identification of individual genes. • He therefore generated congenic mouse stains Identified 2 types of loci: Major (strong) = H-2 Minor (weak) = non-H2 i.e. H-1, H-4, H-Y • Nomenclature- STRAIN.LOCUS (i.e. B10.H-2a or B10.A)

8. Generation of congenic mouse strains “Speed congenics” decrease the number of backcross generations by typing each chromosome for background strain alleles and selecting mice to breed which have the highest number of background genes.

9. H-2 Congenic mouse strains

10. Table 1

11. Figure 1

12. Table 2

13. The forgotten guinea pig Inbred stains of guinea pigs -strain 2 and strain 13 -differ at the I region of MHC Benacerraf (1963) - Guinea Pigs Strain 2 Strain 13 PLL(poly L-lysine) + – GT(glutamic acid/ tyrosine) – +

14. MHC restriction was first shown a year prior to Zinkernagel and Doherty’s study JEM 138:194,1973

15. MHC Restriction

16. 1-2. Zinkernagel, R.M. and Doherty, P.C.Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis. Nature 251:547-548. (1974).

17. People and Places • Rolf Zinkernagel • M.D. Switzerland - • Cerottini & Brunner- developed the 51Cr-release assay • Ph.D. Australian National University (ANU) • Canberra headed by Gordon Ada • Asst. Professor - Scripps • Professor -U. of Zurich • Peter Doherty • Veterinarian • Postdoc-Scotland • ANU • Wistar, ANU, St. Jude’s • Australia

18. Table 1

19. Table 2

20. Figure 1

21. 1-3. Babbitt, B.P., Allen, P.M., Matsueda, G., Haber, E., and Unanue, E.R. Binding of immunogenic peptides to Ia histocompatibility molecules. Nature 317:359-361. (1985).

22. Ir Genes • How to explain lack of a response • Hole in the repertoire • T cells do not exist that are able to respond, involving thymic selection • Determinant Selection • MHC molecules select which determinants they can present

23. Where’s Bruce?

24. Numerous groups had completely failed to find any evidence that antigen associated directly with MHC molecules JI 133:2067(84)

25. Identification of the HEL(46-61)/I-Ak epitope A single HEL tryptic fragment stimulates HEL specific T cells Stimulatory fragment identified as 46-61 Allen, Strydom, and Unanue, PNAS 1984

26. Figure 1

27. Figure 2

28. Figure 3