T cells with variable region Vdelta 1 gammadelta T cell receptors (TCRs) are distributed throughout the human intestinal epithelium and may function as sentinels that respond to self antigens.The expression of a major histocompatibility complex (MHC) class I-related molecule, MICA, matches this localization. MICA and the closely related MICB were recognized by intestinal epithelial T cells expressing diverse Vdelta 1 gammadelta TCRs. These interactions involved the alpha1alpha2 domains of MICA and MICB but were independent of antigen processing. With intestinal epithelial cell lines, the expression and recognition of MICA and MICB could be stress-induced. Thus, these molecules may broadly regulate protective responses by the Vdelta 1 gammadelta T cells in the epithelium of the intestinal tract.