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+ Treg 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+ Treg 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 Treg cells and to ensure mature T-cell quiescence.

Recurrent oral ulcerations following heart transplant in a pediatric patient: A diagnostic dilemma

“…CNIs have been suggested to be the major reason for this increase in autoimmune disease in transplant recipients. CNIs interfere with T‐cell signaling, disrupt thymic T‐cell maturation, and downregulate T regulatory cells . A recent publication demonstrated complete resolution of autoimmune cytopenias after discontinuation of tacrolimus …”

“…CNIs interfere with T-cell signaling, disrupt thymic T-cell maturation, and downregulate T regulatory cells. [20][21][22][23] A recent publication demonstrated complete resolution of autoimmune cytopenias after discontinuation of tacrolimus. 17 Thymectomies, a common consequence of cardiac surgery, may put heart transplant recipients at a higher risk of autoimmune disease, compared to other SOTs.…”

De Novo Food Allergy in Pediatric Recipients of Liver Transplant

“…Calcineurin inhibitors (CI, eg, cyclosporine, tacrolimus) have been implicated and identified as a potentially modifiable risk factor for dnPTFA. Tacrolimus and, with a lower potency, cyclosporin impair the functioning of Treg cells (16)(17)(18), inhibit the production of interleukin-2, decrease interleukin-10 ( 19) and increase interleukin-5. With this immunologic imbalance, when an antigen-presenting cell encounters a food antigen and presents it to a naı ¨ve T cell, the imbalanced immunity results in a T H 2 response (20,21) instead of a Treg cell response, in the suppression of the Thelper cell responses, particularly T H 1 and in the production of immunoglobulin E (IgE) and activation of mast cells and eosinophils.…”