Calcineurin B in CD4+ T Cells prevents autoimmune colitis by negatively regulating the JAK/STAT pathway

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Abstract

Calcineurin (Cn) is a protein phosphatase that regulates the activation of the nuclear factor of activated T-cells (NFAT) family of transcription factors, which are key regulators of T-cell development and function. Here, we generated a conditional Cnb1 mouse model in which Cnb1 was specifically deleted in CD4+ T cells (Cnb1CD4 mice) to delineate the role of the Cn-NFAT pathway in immune homeostasis of the intestine. The Cnb1CD4 mice developed severe, spontaneous colitis characterized at the molecular level by an increased T helper-1-cell response but an unaltered regulatory T-cell compartment. Antibiotic treatment ameliorated the intestinal inflammation observed in Cnb1CD4 mice, suggesting that the microbiota contributes to the onset of colitis. CD4+ T cells isolated from Cnb1CD4 mice produced high levels of IFN? due to increased activation of the JAK2/STAT4 pathway induced by IL-12. Our data highlight that Cn signaling in CD4+ T cells is critical for intestinal immune homeostasis in part by inhibiting IL-12 responsiveness of CD4+ T cells.

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Mencarelli, A., Vacca, M., Khameneh, H. J., Acerbi, E., Tay, A., Zolezzi, F., … Mortellaro, A. (2018). Calcineurin B in CD4+ T Cells prevents autoimmune colitis by negatively regulating the JAK/STAT pathway. Frontiers in Immunology, 9(FEB). https://doi.org/10.3389/fimmu.2018.00261

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