Calcineurin B in CD4(+) T Cells Prevents Autoimmune Colitis by Negatively Regulating the JAK/STAT Pathway

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 (Cnb1(CD4) mice) to delineate the role of the Cn–NFAT pathway in immune homeostasis of the intestine. The Cnb1(CD4) 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 Cnb1(CD4) mice, suggesting that the microbiota contributes to the onset of colitis. CD4(+) T cells isolated from Cnb1(CD4) mice produced high levels of IFNγ 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.