A critical role for protein kinase C-theta-mediated T cell survival in cardiac allograft rejection.
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.
Manicassamy
Santhakumar
S
Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Yin
Dengping
D
Zhang
Zheng
Z
Molinero
Luciana L
LL
Alegre
Marisa-Luisa
ML
Sun
Zuoming
Z
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D060908:CTLA-4 Antigen; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007136:Immunoglobulins / Q000276:immunology; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology; D051020:bcl-X Protein / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018398:Homeodomain Proteins; D007136:Immunoglobulins; D007527:Isoenzymes; D051020:bcl-X Protein; C064658:RAG-1 protein; D023201:CD40 Ligand; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta