Protein kinase C-θ is an early survival factor required for differentiation of effector CD8+ T cells

CD8(+) T cells are crucial for host defense against invading pathogens and malignancies. However, relatively little is known about intracellular signaling events that control the genetic program of their activation and differentiation. Using CD8+ T cells from TCR-transgenic mice crossed to protein kinase C-theta (PKC theta)-deficient mice, we report that PKC theta is not required for Ag-induced CD8(+) T cell proliferation, but is important for T cell survival and. differentiation into functional, cytokine-producing CTLs. Ag-stimulated PKC theta(-/-) T cells underwent accelerated apoptosis associated with deregulated expression of Bcl-2 family proteins and displayed reduced activation of ERKs and JNKs. Some defects in the function of PKC theta(-/-) T cells (poor survival and reduced Bcl-2 and Bcl-x(L) expression, CTL activity, and IFN-gamma expression) were partially or fully restored by coculture with wild-type T cells or by addition of exopnous IL-2, whereas others (increased Bim(EL) expression and TNF-alpha production) were not. These findings indicate that PKC theta, although not essential for initial Ag-induced proliferation, nevertheless plays an important role in promoting and extending T cell survival, thereby enabling the complete genetic program of effector CD8(+) differentiation. The requirement for PKC theta in different types of T cell-dependent responses may, therefore, depend on the overall strength of signaling by the TCR and costimulatory receptors and may reflect, in addition to its previously established role in activation, an important, hitherto unappreciated, role in T cell survival.