A critical role for protein kinase C-theta-mediated T cell survival in cardiac allograft rejection

作者：Manicassamy Santhakumar; Yin Dengping; Zhang Zheng; Molinero Luciana L; Alegre Marisa Luisa; Sun Zuoming^*

来源：The Journal of Immunology, 2008, 181(1): 513-520.

Protein kinase C (PKC)-theta mediates the critical TCR signals required for T cell activation. Previously, we have shown that in response to TCR stimulation, PKC-theta(-/-) T cells undergo apoptosis due to greatly reduced levels of the anti-apoptotic molecule, BCl-X-L. In this study, we demonstrate that PKC-theta-regulated 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-theta(-/-) T cells failed to promote rejection. Transgenic expression of BCl-X-L in PKC-theta(-/-) T cells was sufficient to restore cardiac allograft rejection, suggesting that PKC-theta-regulated survival is required for T cell-mediated cardiac allograft rejection in this adoptive transfer model. In contrast to adoptive transfer experiments, intact PKC-theta(-/-) mice displayed delayed, but successful cardiac allograft rejection, suggesting the potential compensation for PKC-theta function. Finally, a subtherapeutic 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-theta(-/-) mice. Thus, in combination with other treatments, inhibition of PKC-theta may facilitate achieving long-term survival of allografts.

• 出版日期2008-7-1
• 单位西北大学