THE FUNCTIONAL BASIS OF MINOR HISTOCOMPATIBILITY LOCI

This work addresses the functional basis of classical minor histocompa tibility (H) loci. We focus on the H-3 locus, which is actually a comp lex genetic unit to which the phenotypic trait of tissue rejection, ge nes whose products stimulate specific subsets of T cells, and Ir genes have been mapped. To clarify how these genes relate to one another an d to the trait of tissue rejection, strains of intra-H-3 recombinant m ice were produced and analyzed. These mice allowed us to selectively e licit immune responses to Ag (referred to as type I Ag) that stimulate MHC class I-restricted CTL, or Ag (referred to as type II Ag) that st imulate MHC class II-restricted Th. The splitting of H-3 in this manne r resulted in a dramatic diminution of the skin allograft response, an d with rare exception, an elimination of the CTL response after spleen cell immunization. A selective response to type I Ag resulted in slow , incomplete skin allograft rejection that demonstrated both CD4+ cell -dependent and -independent components. A selective response to the ty pe II Ag failed to result in allograft rejection. The type II Ag did, however, act as an Ir gene that determined whether responses to type I Ag could occur. Altogether, the results indicate that the trait of ti ssue rejection associated with H-3 is a consequence of the strongly sy nergistic effects of Th-CTL collaboration induced by products of type I and type II genes. Moreover, the results suggest a genetic explanati on for some of the Ir gene effects associated with H-3.