Requirement of calcineurin a beta for the survival of naive T cells.

Calcineurin (Cn) is a Ca2+/calmodulin-dependent phosphatase that dephosphorylates and activates NFAT, a transcription factor essential for T cell activation. T lymphocytes predominantly express the calcineurin Abeta (CnAbeta) isoform, and the deletion of the CnAbeta gene results in defective T cell proliferation and IL-2 production in response to TCR stimulation. In this study, we show that CnAbeta enhances the spontaneous survival of naive T cells by maintaining high levels of Bcl-2, a critical homeostatic survival factor for naive T cells. T cells obtained from CnAbeta-/- mice displayed accelerated spontaneous apoptosis. The observed apoptosis of the CnAbeta-/- T cells was prevented by IL-7 and IL-15, two cytokines critical for the homeostatic survival of naive T cells. Furthermore, CD4+ or CD8+ single positive CnAbeta-/- thymocytes also underwent accelerated apoptosis. However, no obvious difference in the apoptosis of CD4+CD8+ double positive thymocytes was observed between CnAbeta-/- and wild-type mice, suggesting a specific function of CnAbeta in the survival of single positive T cells. Bcl-2 levels were found to be significantly lower in CnAbeta-/- T cells. Transgenic expression of Bcl-xL restored the survival of the CnAbeta-/- T cells. Thus, in addition to its role in mediating TCR signals essential for T cell activation, CnAbeta is also required for the homeostatic survival of naive T cells.