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.
Manicassamy
Santhakumar
S
Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Gupta
Sonal
S
Huang
Zhaofeng
Z
Molkentin
Jeffery D
JD
Shang
Weirong
W
Sun
Zuoming
Z
D000818:Animals; D017209:Apoptosis; D015704:CD4 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D016827:CD8 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics; D019409:Interleukin-15 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
C494812:Bcl2l1 protein, mouse; D015704:CD4 Antigens; D016827:CD8 Antigens; D019409:Interleukin-15; D015851:Interleukin-7; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D051020:bcl-X Protein; C052617:Bcl2 protein, mouse; D019703:Calcineurin