THE GENETIC-ORIGIN OF MINOR HISTOCOMPATIBILITY ANTIGENS

The purpose of this study was to elucidate the genetic origin of minor histocompatibility (H) antigens. Toward this end common inbred mouse strains, distinct subspecies, and species of the subgenus Mus were exa mined for expression of various minor H antigens. These antigens were encoded by the classical minor H loci H-3 and H-4 or by newly identifi ed minor H antigens detected as a consequence of mutation. Both minor H antigens that stimulate MHC class I-restricted cytotoxic T cells (Tc ) and antigens that stimulate MHC class II-restricted helper T cells ( Th) were monitored. The results suggested that strains of distinct anc estry commonly express identical or cross-reactive antigens. Moreover, a correlation between the lack of expression of minor H antigens and ancestral heritage was observed. To address whether the antigens found on unrelated strains were allelic with the sensitizing minor H antige ns or a consequence of antigen cross-reactivity, classical genetic seg regation analysis was carried out. Even in distinct subspecies and spe cies, the minor H antigens always mapped to the site of the appropriat e minor H locus. Together the results suggest: 1) minor H antigen sequ ences are evolutionarily stable in that their pace of antigenic change is slow enough to predate subspeciation and speciation; 2) the minor H antigens originated in the inbred strains as a consequence of a rare polymorphism or loss mutation carried in a founder mouse stock that c aused the mouse to perceive the wild-type protein as foreign; 3) there is a remarkable lack of antigenic cross-reactivity between the define d minor H antigens and other gene products.