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A critical role for PKC‐theta‐mediated T cell survival in cardiac allograft rejection
Author(s) -
Sun Zuoming,
Manicassamy Santhkumar,
Yin Dengping,
Molinero Luciana L,
Alegre MarisaLuisa Alegre
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.662.8
Subject(s) - cd154 , adoptive cell transfer , protein kinase c , t cell , transplantation , microbiology and biotechnology , apoptosis , t cell receptor , biology , immunology , chemistry , medicine , signal transduction , immune system , cd40 , cytotoxic t cell , in vitro , biochemistry
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. Here 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 (WT) 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 sub‐therapeutic dose of anti‐CD154 antibody, that was not sufficient to prevent cardiac allograft rejection in the WT 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.