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

Andrea Mencarelli, Maurizio Vacca, Hanif Javanmard Khameneh, Enzo Acerbi, Alicia Tay, Francesca Zolezzi, Michael Poidinger, Alessandra Mortellaro

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 (Cnb1CD4mice) to delineate the role of the Cn-NFAT pathway in immune homeostasis of the intestine. The Cnb1CD4mice 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 Cnb1CD4mice, suggesting that the microbiota contributes to the onset of colitis. CD4+T cells isolated from Cnb1CD4mice 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.