Divergent effects of calcineurin Aβ on regulatory and conventional T-cell homeostasis

Calcineurin (CN) is a phosphatase that activates nuclear factor of activated T cells (NFAT). While the CN inhibitors cyclosporine A (CsA) and tacrolimus (FK506) can prevent graft rejection, they also cause inflammatory diseases. We investigated the role of calcineurin using mice deficient in the CN catalytic subunit Aβ (CNAβ). Cnab^-/- mice exhibit defective thymocyte maturation, splenomegaly and hepatomegaly. Further, as Cnab^-/- mice age, they exhibit spontaneous T-cell activation and enhanced production of proinflammatory cytokines (IL-4, IL-6, and IFNγ). FOXP3⁺ T_reg cells were significantly decreased in Cnab^-/- mice likely contributing to increased T-cell activation. Interestingly, we found that CNAβ is critical for promotion of BCL-2 expression in FOXP3⁺ T_reg and for permitting TGFβ signaling, as TGFβ induces FOXP3 in control but not in Cnab^-/- T-cells. Together, these data suggest that CNAβ is important for the production and maintenance of T_reg cells and to ensure mature T-cell quiescence.