A Critical role for protein kinase C-θ-mediated T cell survival in cardiac allograft rejection

Protein kinase C (PKC)-θ mediates the critical TCR signals required for T cell activation. Previously, we have shown that in response to TCR stimulation, PKC-θ^-/- T cells undergo apoptosis due to greatly reduced levels of the anti-apoptotic molecule, Bcl-x_L. In this study, we demonstrate that PKC-θ-reguIated expression of Bcl-x_L is essential for T cell-mediated cardiac allograft rejection. Rag1^-/- mice reconstituted with wild-type T cells readily rejected fully mismatched cardiac allografts, whereas Rag1^-/- mice reconstituted with PKC-θ^-/- T cells failed to promote rejection. Transgenic expression of Bcl-xL in PKC-θ^-/- T cells was sufficient to restore cardiac allograft rejection, suggesting that PKC-θ-regulated survival is required for T cell-mediated cardiac allograft rejection in this adoptive transfer model. In contrast to adoptive transfer experiments, intact PKC-θ^-/- mice displayed delayed, but successful cardiac allograft rejection, suggesting the potential compensation for PKC-θ function. Finally, a subthera-peutic dose of anti-CD154 Ab or CTLA4-Ig, which was not sufficient to prevent cardiac allograft rejection in the wild-type mice, prevented heart rejection in the PKC-θ^-/- mice. Thus, in combination with other treatments, inhibition of PKC-θ may facilitate achieving long-term survival of allografts.