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A Critical Role for Protein Kinase C--Mediated T Cell Survival in Cardiac Allograft Rejection¹

Santhakumar Manicassamy^2,, Dengping Yin^2,, Zheng Zhang, Luciana L. Molinero^¶, Marisa-Luisa Alegre^¶ and Zuoming Sun^3,*,

^* Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010; Department of Microbiology & Immunology, Medical School of the University of Illinois, Chicago, IL 60612; Department of Surgery, Division of Heptatobiliary Surgery and Transplantation, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Surgery-Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and ^¶ Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL 60637

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

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from American Cancer Society of Illinois Division, Schweppe Foundation, UIC University of Illinois Cancer Center, and UIC Institutional Review Board, and National Institutes of Health Grant R01-AI053147.

² S.M. and D.Y. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Zuoming Sun, Division of Immunology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010. E-mail address: zuoming{at}uic.edu

⁴ Abbreviations used in this paper: PKC, protein kinase C; Bcl-x_L^Tg, Bcl-x_L transgenic; Treg, T regulatory; WT, wild type.