Calcineurin, a protein phosphatase activated by Ca2+-calmodulin, is involved in activation of NFAT by its dephosphorylation.Calcineurin inhibitors such as cyclosporine A (CsA) and FK506 are potent inhibitors of T cell responses and are commonly used to prevent graft rejection.Although these agents are effective in treating transplant patients for transplant acceptance, long-term side effects include frequent infections and malignancies.CsA also inhibits Foxp3 expression in T cells through inhibition of NFATc and IL-2 suggesting that calcineurin signaling is important for Treg cell generation.NFAT molecules are critical regulator of T cell anergy and response.NFAT also binds to the Tgfb1 promoter and induces its expression under tolerogenic conditions.These studies suggest that calcineurin plays multiple roles in multiple cell types.Dysregulation of these processes could lead to inflammation and inflammation-induced cancers such as lymphoma and IBD-associated colon cancer.Consistently, T cells deficient in calcineurin Aβ (CnAβ) are hypo-responsive to TCR stimulation in young mice.However, T cells undergo spontaneous activation in older Cnab-/-mice, which develop metastatic lymphomas.CnA-deficient mice exhibit splenomegaly, hepatomegaly and metastatic lymphomas as the mice age (aiter 6 months).Both CD4+ and CD8+ T cells in the spleens of Cnab-/-mice are activated.We have also observed that FOXP3+ Treg cells are decreased while mature activated CD4+ and CD8+ T cells are increased in older Cnab-/-mice compared to young Cnab-/-mice.These data also show that CnAβ is important for the development and homeostasis of mature T cells and Trig cells.In the absence of CnAβ, a defective T cell regulatory environment might lead to activation and expansion of T cells so that the mice would eventually develop lymphomas due to altered homeostasis.