ORAL TOLERANCE TO HAPTENS - INTESTINAL EPITHELIAL-CELLS FROM 2,4-DINITROCHLOROBENZENE-FED MICE INHIBIT HAPTEN-SPECIFIC T-CELL ACTIVATION IN-VITRO

The mechanisms underlying the induction of immunological tolerance aft er feeding soluble exogenous antigens, including proteins and haptens, are still unclear. Using a model of oral tolerance to the contact-sen sitizing hapten 2,4-dinitrochlorobenzene (DNCB), we have compared the ability of intestinal epithelial cells and of Peyer's patch APC to pre sent DNCB in vitro or ex vivo after oral feeding, to specific peripher al lymph node T cells from DNCB-sensitized mice. In contrast to Peyer' s patch APC, which induce efficient hapten-specific T cell activation upon exposure to the hapten either in vitro or in vivo, mature MHC cla ss-II-positive intestinal epithelial cells were unable to induce T cel l activation in either case. Interestingly, enterocytes from DNCB-fed mice exerted a dramatic inhibitory effect on the proliferative respons e of hapten-primed T cells in response to dinitrobenzene sulfonate pre sented by syngeneic spleen cells. This inhibitory effect, which was al so observed with supernatant of intestinal epithelial cells from DNCB- fed mice, could be reversed by neutralizing anti-transforming growth f actor (TGF)-beta antibodies. In addition, pre-incubation of hapten-sen sitized T cells with enterocytes from DNCB-fed mice induced T cell ane rgy, which could be reversed by exogenous interleukin-2 or interleukin -4. These data demonstrate that intestinal epitheliaI cells activated in vivo by oral administration of DNCB are able to block proliferation of activated T cells through secretion of immunosuppressive cytokines such as TGF-beta. It is proposed that intestinal epithelial cells may play a significant role in oral tolerance by limiting T cell-mediated hypersensitivity responses.