Activation induced cell death (AICD) has been proposed to serve as a mechanism to limit T lymphocyte proliferation induced by antigenic stimulation. Heat shock proteins (hsp60 and hsp70) expressed on oral tumor cells serve as ligands for peripheral blood cdT lymphocytes. Tumor cell lysis by cdT lymphocytes is mediated via recognition of hsp expressed on tumor cells. In the present study, we report that upon stimulation with hsp, cdT lymphocytes isolated from oral cancer patients undergo AICD as confirmed by DNA ploidy, annexin V staining and confocal microscopy. In cocultures of cdT lymphocytes and tumor cells, addition of antihsp60 and antihsp70 MAb, but not anti-Fas MAb (ZB4), inhibited DNA fragmentation of cdT lymphocytes. Flow cytometric analysis revealed a down regulation of Fas expression on cdT lymphocytes upon incubation with hsp60 and hsp70. Increased expression of iNOS was observed in hsp-stimulated cdT lymphocytes. Addition of monomethyl L-arginine monoacetate, competitive inhibitor of NOS, inhibited nitric oxide (NO) production and apoptosis of cdT lymphocytes induced by hsp60 and hsp70. The NO-induced apoptosis of cdT lymphocytes involves activation of caspase-9 and loss of mitochondrial membrane potential. The present study explains a novel strategy adopted by tumor cells to evade immune recognition by cdT lymphocytes. ' 2006 Wiley-Liss, Inc.