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

Santhakumar Manicassamy, Dengping Yin, Zheng Zhang, Luciana L. Molinero, Marisa Luisa Alegre, Zuoming Sun

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

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-xL. In this study, we demonstrate that PKC-θ-reguIated 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-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.

Original languageEnglish (US)
Pages (from-to)513-520
Number of pages8
JournalJournal of Immunology
Volume181
Issue number1
DOIs
StatePublished - 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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