CD8-DEPENDENT CTL REQUIRE CO-ENGAGEMENT OF CD8 AND THE TCR FOR PHOSPHATIDYLINOSITOL HYDROLYSIS, BUT CD8-INDEPENDENT CTL DO NOT AND CAN KILLIN THE ABSENCE OF PHOSPHATIDYLINOSITOL HYDROLYSIS

Most instances of MHC class I recognition and target cell killing by C D8(+) CTL require the involvement of CD8, The role of CD8 in these eve nts may be both for adhesion of the CTL with the APC, as well as for s ignal transduction through the TCR, The precise mechanism by which CD8 mediates signal transduction remains enigmatic, Similarly, it is uncl ear whether only the CD8 molecules which bind to the same class I mole cule as the TCR contribute to signaling in the T cell responding to an tigen, We have investigated the requirement for co-engagement of CD8 a nd the TCR in the induction of the hydrolysis of phosphatidylinositol- 4,5-bisphosphate (PIP2) during the interaction of CTL and APC transfec ted with either wild-type or mutant (CD8 non-binding) class I molecule s, Our results show that for conventional CD8-dependent killing co-eng agement of both CD8 and the TCR is required to initiate PIP2 hydrolysi s, This requirement for co-engagement, however, can be overcome by a h igh density of ligand, such as that provided by high concentrations of exogenous peptide, In such situations, the binding of CD8 to non-anti genic class I molecules can elicit PIP2 hydrolysis. Therefore, during interactions between CTL and APC, which generally occur at low concent rations of antigenic peptide, triggering of PIP2 hydrolysis requires T CR and CD8 co-engagement, and the binding of CD8 to non-antigenic clas s I molecules does not contribute significantly to signaling within th e T cell, Upon interaction of CD8 independent CTL with APC which expre ss the mutant alloantigenic molecule, but do not express any non-antig enic class I molecules, there is no PIP2 hydrolysis.