Distant relatives of major histocompatibility complex (MHC) class I molecules, human MICA and MICB, function as stress-induced antigens that are broadly recognized by intestinal epithelial ␥␦ T cells. They may thus play a central role in the immune surveillance of damaged, infected, or otherwise stressed intestinal epithelial cells. However, the generality of this system in evolution and the mode of recognition of MICA and MICB are undefined. Analysis of cDNA sequences from various 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 alterations are several deletions and frequent amino acid substitutions in the putative ␣-helical regions of the ␣ 1 ␣ 2 domains. However, 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 ␣ 1 ␣ 2 domains, they were recognized by diverse human intestinal epithelial ␥␦ T cells that are restricted by MICA and MICB. Thus, MIC molecules represent a family of MHC proteins that are structurally diverse yet appear to be functionally conserved. The promiscuous mode of ␥␦ T cell recognition of these antigens may be explained by their sharing of a single conserved interaction site.The extended family of major histocompatibility complex (MHC) class I-related proteins serves a variety of immunological functions, among which those of the polymorphic MHC class I molecules are paramount (1). These heterodimers of a membrane-anchored class I chain and soluble  2 -microglobulin ( 2 m) present intracellularly processed peptide antigens to cytotoxic T cells with ␣ T cell receptors (TCRs), thus facilitating the elimination of pathogen-infected cells (2). Class I chains have three extracellular domains, of which the membrane-distal ␣ 1 ␣ 2 domains fold to bind peptide between two ␣-helices on the platform of a -pleated sheet (3, 4). Both the ␣-helices and bound peptide are involved in extensive contacts made by ␣-and -chain variable regions of antigen-specific TCRs (5, 6). The membrane-proximal ␣ 3 domain includes contact residues for  2 m and the main binding site for the T cell coreceptor CD8 (3). These structure-function relationships, however, are greatly modified among molecules that are distantly related to MHC class I (7). Among these are the CD1 molecules, which present mycobacterial lipids and glycolipids to some ␣ T cells (8,9). A more recent example is represented by the human MHC class I-related chains A and B (MICA and MICB), which function as stress antigens that are broadly recognized by intestinal intraepithelial ␥␦ T cells (10).Although MICA and MICB are encoded in the MHC, they are highly divergent from conventional MHC class I, with an average of only 27% amino acid sequence identity in the extracellular ␣ 1 ␣ 2 ␣ 3 domains (11). MICA and MICB themselves are closely related...