TY - JOUR
T1 - The transcription factor NFATc1 supports the rejection of heterotopic heart allografts
AU - Baur, Johannes
AU - Otto, Christoph
AU - Steger, Ulrich
AU - Klein-Hessling, Stefan
AU - Muhammad, Khalid
AU - Pusch, Tobias
AU - Murti, Krisna
AU - Wismer, Rhoda
AU - Germer, Christoph Thomas
AU - Klein, Ingo
AU - Müller, Nora
AU - Serfling, Edgar
AU - Avots, Andris
N1 - Publisher Copyright:
© 2018 Baur, Otto, Steger, Klein-Hessling, Muhammad, Pusch, Murti, Wismer, Germer, Klein, Müller, Serfling and Avots.
PY - 2018/6/12
Y1 - 2018/6/12
N2 - The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8+ T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis and the expression of numerous lymphokines, chemokines, and their receptors, including Cxcr3 that supports the rejection of allogeneic heart transplants. These findings favors NFATc1 as a molecular target for the development of new strategies to control the cytotoxicity of T cells upon organ transplantation.
AB - The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8+ T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis and the expression of numerous lymphokines, chemokines, and their receptors, including Cxcr3 that supports the rejection of allogeneic heart transplants. These findings favors NFATc1 as a molecular target for the development of new strategies to control the cytotoxicity of T cells upon organ transplantation.
KW - CD8 T cells
KW - ChIPseq
KW - Heterologous
KW - Metabolism
KW - NFATc1
KW - Transplantation
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U2 - 10.3389/fimmu.2018.01338
DO - 10.3389/fimmu.2018.01338
M3 - Article
AN - SCOPUS:85048341945
SN - 1664-3224
VL - 9
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - JUN
M1 - 1338
ER -