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

Manicassamy S, Yin D, Zhang Z, Molinero LL, Alegre ML, Sun Z
J Immunol. 2008 181 (1): 513-20

PMID: 18566417 · PMCID: PMC2488962 · DOI:10.4049/jimmunol.181.1.513

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-xL. In this study, we demonstrate that PKC-theta-regulated expression of Bcl-xL 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-xL 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.

MeSH Terms (21)

Animals Antibodies, Monoclonal Antigens, CD bcl-X Protein CD40 Ligand Cells, Cultured Cell Survival CTLA-4 Antigen Female Graft Rejection Heart Transplantation Homeodomain Proteins Immunoglobulins Isoenzymes Lymphocyte Culture Test, Mixed Mice Mice, Knockout Protein Kinase C Protein Kinase C-theta T-Lymphocytes Transplantation, Homologous

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