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 Citations (Scopus)

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-x L. In this study, we demonstrate that PKC-θ-reguIated 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-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
StatePublished - Dec 1 2008
Externally publishedYes

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Protein Kinase C
Allografts
Cell Survival
T-Lymphocytes
Adoptive Transfer
Apoptosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Manicassamy, S., Yin, D., Zhang, Z., Molinero, L. L., Alegre, M. L., & Sun, Z. (2008). A Critical role for protein kinase C-θ-mediated T cell survival in cardiac allograft rejection. Journal of Immunology, 181(1), 513-520.

A Critical role for protein kinase C-θ-mediated T cell survival in cardiac allograft rejection. / Manicassamy, Santhakumar; Yin, Dengping; Zhang, Zheng; Molinero, Luciana L.; Alegre, Marisa Luisa; Sun, Zuoming.

In: Journal of Immunology, Vol. 181, No. 1, 01.12.2008, p. 513-520.

Research output: Contribution to journalArticle

Manicassamy, S, Yin, D, Zhang, Z, Molinero, LL, Alegre, ML & Sun, Z 2008, 'A Critical role for protein kinase C-θ-mediated T cell survival in cardiac allograft rejection', Journal of Immunology, vol. 181, no. 1, pp. 513-520.
Manicassamy, Santhakumar ; Yin, Dengping ; Zhang, Zheng ; Molinero, Luciana L. ; Alegre, Marisa Luisa ; Sun, Zuoming. / A Critical role for protein kinase C-θ-mediated T cell survival in cardiac allograft rejection. In: Journal of Immunology. 2008 ; Vol. 181, No. 1. pp. 513-520.
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