DIVERSIFICATION, EXPRESSION, AND GAMMA-DELTA T-CELL RECOGNITION OF EVOLUTIONARILY DISTANT MEMBERS OF THE MIC FAMILY OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I-RELATED MOLECULES

Distant relatives of major histacompatibility complex (MHC) class I mo lecules, human MICA and MICB, function as stress-induced antigens that are broadly recognized by intestinal epithelial y delta T cells. They may thus play a central role in the immune surveillance of damaged, i nfected, or otherwise stressed intestinal epithelial cells. However, t he generality of this system in evolution and the mode of recognition of MICA and MICB are undefined. Analysis of cDNA sequences from variou s primate species defined translation products that are homologous to MICA and MICB. All of the MIC polypeptides have common characteristics , although they are extraordinarily diverse. The most notable alterati ons are several deletions and frequent amino acid substitutions in the putative alpha-helical regions of the alpha(1)alpha(2) domains. Howev er, the primate MIC molecules were expressed on the surfaces of normal and transfected cells. Moreover, despite their sharing of relatively few identical amino acids in potentially accessible regions of their a lpha(1)alpha(2) domains, they were recognized by diverse human intesti nal epithelial y delta T cells that are restricted by MICA and MICB. T hus, MIC molecules represent a family of MHC proteins that are structu rally diverse yet appear to be functionally conserved. The promiscuous mode of y delta T cell recognition of these antigens may be explained by their sharing of a single conserved interaction site.