Background & Aims: Intestinal smooth muscle cells (ISMCs) express major histocompatibility complex II (MHC II) and intercellular adhesion molecule 1 (ICAM-1) after exposure to interferon gamma (IFN-gamma), T lymphocytes invade the intestinal musculature during Crohn's disease or pseudo-obstruction. The aim of this study was to determine whether ISMCs activate syngeneic T cells via MHC II and ICAM-1, Methods: Cultured murine ISMCs were exposed to IFN-gamma for 72 hours and analyzed for Mac-1 (CD11B CD18) antigen, MHC II, and ICAM-1 expression using enzyme-linked immunosorbent assay and fluorescence-activated cell sorter scan, T lymphocytes from mesenteric lymph nodes of ovalbumin-sensitized mice were examined for their ability to proliferate after coculture with IFN-gamma-pretreated and ovalbumin-pretreated ISMCs using [H-3]thymidine incorporation, Results: ISMCs expressed smooth muscle alpha-actin before and after IFN-gamma exposure, No macrophages were identified in these cultures, Exposure to IFN-gamma and ovalbumin for 72 hours induced MHC II and ICAM-1 expression; these treated ISMCs induced T-cell proliferation, whereas untreated ISMCs did not, T-cell proliferation was markedly enhanced by adding interleukin 2 and was blocked by antibodies against MHC II and ICAM-1, Conclusions: ISMCs activate T lymphocytes in an MHC II-linked manner and thus possess the ability to modulate immune function in the gut.