T cells with variable region V(delta)1 gamma delta 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 MICE were recognized by intestinal epithelial T cells expressing diverse V(delta)1 gamma delta TCRs, These interactions involved the alpha 1 beta 2 domains of MICA and MICE but were independent of antigen processing. With intestinal epithelial cell lines, the expression and recognition of MICA and MICE could be stress-induced. Thus, these molecules may broadly regulate protective responses by the V(delta)1 gamma delta T cells in the epithelium of the intestinal tract.