THE ROLE OF PROTEIN-KINASE-C IN CD8(-LYMPHOCYTE EFFECTOR RESPONSES() T)

Rare CD8(+) T cells present in beta(2)microglobulin-deficient (beta(2) m(-/-)) mice reject allogeneic tumors but not syngeneic wild-type tumo rs, The lack of syngeneic tumor rejection in vivo is correlated with a partial response of beta(2)m(-/-) CD8(+) cell lines to syngeneic tumo r cells in vitro, This partial response is characterized by perforin/g ranzyme-mediated cytolytic activity in the absence of cytokine secreti on or proliferation, Allogeneic tumors induce cytolysis, cytokine secr etion, and proliferation, Cytokine secretion may therefore be an impor tant effector mechanism for tumor rejection by CD8(+) T cells, To dete rmine the missing signaling events needed for cytokine secretion as we ll as the events inducing the isolated cytotoxic response, we attempte d to restore cytokine secretion of beta(2)m(-/-) CD8(+) cells to synge neic MHC class I, Phorbol ester and syngeneic tumor cells acted synerg istically to induce full responsiveness of beta(2)m(-/-) CD8(+) cells, However, this synergistic induction of cytokine secretion used a diff erent pathway than that induced by alloantigen, protein kinase C (PKC) inhibitor prevented the syngeneic class I plus PMA-induced cytokine s ecretion, but not allo-class I-induced cytokine secretion, In contrast to the PKC independent alloantigen-induced cytokine secretion, cytoly sis of both allogeneic and syngeneic targets was PKC dependent, The di fferential dependence of effector functions on PKC activation was also found in beta(2)m(+/+) CD8(+) T cells, Thus, two distinct signaling p athways (PKC dependent and PKC independent) may ultimately converge to induce cytokine secretion in CD8(+) cells, The TCR engagement-initiat ed pathway is PKC independent, whereas the phorbol ester-activated pat hway is PKC dependent.