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Requirement of Calcineurin Aβ for the Survival of Naive T Cells¹

Santhakumar Manicassamy, Sonal Gupta, Zhaofeng Huang, Jeffery D. Molkentin, Weirong Shang and Zuoming Sun^2,*,

^* Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010; Department of Microbiology and Immunology, Medical School of the University of Illinois, Chicago, IL 60612; Division of Molecular Cardiovascular Biology, Department of Pediatrics, Children’s Hospital Medical Center, Cincinnati, OH 45229; and Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA 30308

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 Aβ (CnAβ) isoform, and the deletion of the CnAβ gene results in defective T cell proliferation and IL-2 production in response to TCR stimulation. In this study, we show that CnAβ 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 CnAβ^–/– mice displayed accelerated spontaneous apoptosis. The observed apoptosis of the CnAβ^–/– 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 CnAβ^–/– thymocytes also underwent accelerated apoptosis. However, no obvious difference in the apoptosis of CD4⁺CD8⁺ double positive thymocytes was observed between CnAβ^–/– and wild-type mice, suggesting a specific function of CnAβ in the survival of single positive T cells. Bcl-2 levels were found to be significantly lower in CnAβ^–/– T cells. Transgenic expression of Bcl-x_L restored the survival of the CnAβ^–/– T cells. Thus, in addition to its role in mediating TCR signals essential for T cell activation, CnAβ is also required for the homeostatic survival of naive T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health R01-AI053147.

² Address correspondence and reprint requests to Dr. Zuoming Sun, Division of Immunology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010. E-mail address: zsun{at}coh.org

³ Abbreviations used in this paper: Cn, calcineurin; AICD, activation-induced cell death; CnA, calcineurin subunit A (catalytic and calmodulin binding); CnB, calcineurin subunit B (Ca²⁺ binding regulatory); PKC-, protein kinase C ; Tg, transgenic; WT, wild type.