Discovering the role of the major histocompatibility complex in the immuneresponse

The discovery that genes in the major histocompatibility complex (MHC) play an important role in the immune response depended on the chance interactio n of several unrelated events. The first, and most important, was the decis ion by Michael Sela to synthesize a series of branched, multichain, synthet ic polypeptides based on a backbone of poly-l-lysine. The prototype compoun d, (T,G)-A-L, was tipped with short random sequences of tyrosine and glutam ic acid. This resulted in a restricted range of antigenic determinants comp osed of only two or three amino acids with a variable length-ideal for bind ing to the peptide binding groove of MHC class II molecules. The second was the decision by John Humphrey to immunize various strains of rabbits with this synthetic polypeptide. Two of these rabbit strains showe d very large quantitative differences in antibody response to (T,G)-A-L. In transferring this system to inbred mouse strains, the third bit of good fo rtune was the availability at the National Institute of Medical Research, i n Mill Hill (London), of the CBA (H2(k)) and C57 (H2(b)) strains. The H2(b) haplotype is the only one mediating a uniform high antibody response to (T ,G)-A-L. The fourth critical ingredient was the availability of numerous co ngenic and H2 recombinant inbred strains of mice produced earlier by Snell, Stimpfling, Shreffler, and Klein. A search for congenic pairs of mice expr essing the responder and nonresponder H2 haplotypes on the same background revealed that these strains responded as a function of their H2 haplotype, not of their inbred background. Extensive studies in a variety of inbred st rains carrying recombinant H2 haplotypes, as well as a four-point linkage c ross, mapped immune response to (T,G)A-L within the murine MHC, between the K and Ss loci. The demonstration that stimulation in the mixed lymphocyte reaction (MLR) m apped to the same region quickly led to attempts to produce antisera in con genic H2 recombinant strain combinations. These antisera identified I-regio n associated (Ia) antigens. Immunoprecipitation and blocking studies showed that the gene products controlling specific immune responses, the mixed ly mphocyte reaction, and the structure of Ia antigens were one and the same-n ow designated as the I-A MHC class II molecules. These antisera and inbred strains enabled Unanue to demonstrate the peptide binding function of class II MHC molecules.