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

Abstract

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.