MHC Restriction and IR genes January 15, 2007. 1-1. McDevitt, H.O. and Chinitz, A. Genetic control of the antibody response: Relationship between immune.

MHC Restriction and IR genes

January 15, 2007

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).

It all began with some rabbits

SandylopHimalayan

and some antigensSynthetic polypeptide antigens-branched multichain synthetic polypeptides-not defined structures-(T,G)-A-L; (H,G)-A-L; (P,G)-A-L

Michael Sela-Weissman Institute for Sciences, Rehovot, Israel

R

R

R R

R

Poly-L -lysine

Poly-D,L -alanine

R=poly (tyrosine,glutamine acid =poly (histidine,glutamic acid) =poly (proline,glutamic acid)

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

It all began with some rabbits

Sandylop:(Mill Hill)Non-responder to(T,G)-A-L

Himalayan:(Israel)

Responder to(T,G)-A-L

MHC Congenic Mouse Strains1948- 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)

Generation of congenic mouse strains

Backcross generations (n)

Probability of homozygosity

(p)

4 0.875

8 0.992

12 0.999

“Speed congenics” decrease the number ofbackcross generations by typing each chromosome for background strain alleles and selecting mice to breed which have the highest number of background genes.

H-2 Congenic mouse strains

Strain H-2haplotype

Origin ofbackground

MHC

A a A -A.BY b A BrackyuryA.CA f A CaracalA.SW s A SwissBALB/c d BALB/c BALB/cBALB.B b BALB/c C57Bl/10BALB.K k BALB/c AKRB6.AKR-H-2k k C57Bl/6 AKRB6.SJL s C57Bl/6 SJLB10 b C57Bl/10 C57Bl/10B10.A a C57Bl/10 AB10.D2 d C57Bl/10 DBA/2B10.M f C57Bl/10 OutbredB10.BR k C57Bl/10 C57BRB10.SM v C57Bl/10 SMB10.RIII r C57Bl/10 RIIIB10.PL u C57Bl/10 PL/JC3H k C3H C3HC3H.SW b C3H SwissC3H.NB p C3H NBD1.C d DBA/1 BALB/cD1.LP b DBA/1 LPLP.RIII r LP RIII

Table 1

Figure 1

Table 2

The forgotten guinea pig

Benacerraf (1963) - Guinea PigsStrain 2 Strain 13

PLL(poly L-lysine) + –

GT(glutamic acid/ tyrosine) – +

Inbred stains of guinea pigs -strain 2 and strain 13 -differ at the I region of MHC

MHC restriction was first shown a year prior to Zinkernagel and Doherty’s study

JEM 138:194,1973

MHC Restriction

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).

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

Table 1

Table 2

Figure 1

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).

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

Where’s Bruce?

Numerous groups had completely failed to find any evidence that antigen

associated directly with MHC molecules

JI 133:2067(84)

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

Figure 1

Figure 2

Figure 3