An effective immune response requires the expansion and survival of a large number of activated T cells. This study compared the role of protein kinase C (PKC)theta and associated signaling molecules in the survival of activated primary CD4(+) vs CD8(+) murine T cells. We demonstrate that the absence of PKC theta resulted in a moderate survival defect in CD4(+) T cells and a striking survival defect of CD8(+) T lymphocytes. CD8(+) T cells lacking the c-Rel, but not the NF-kappa B1/p50, member of the NF-kappa B family of transcription factors displayed a similar impairment in cell survival as PKC theta(-/-) CD8(+) T lymphocytes. This implicates c-Rel as a key target of PKC theta-mediated survival signals in CD8(+) T cells. In addition, both c-Rel(-/-) and PKC theta(-/-) T cells also displayed impaired expression of the antiapoptotic Bcl-x(L) protein upon activation. Changes in Bcl-x(L) expression, however, did not correlate with the survival of CD4(+) or CD8(+) lymphocytes. The addition of protein kinase B-mediated survival signals could restore partially CD4(+) T cell viability, but did not dramatically influence CD8(+) survival. Active protein kinase B was also unable to restore proliferative responses in CD8(+) PKC theta(-/-) IF cells. The survival of CD4(+) and CD8(+) T cells deficient in either PKC theta or c-Rel, however, was promoted by the addition of IL-2. Collectively, these data demonstrate that CD4(+) and CD8(+) T cell survival signals are differentially programmed.