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.