Divergent effects of calcineurin Aβ on regulatory and conventional T-cell homeostasis.
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(+) T(reg) 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(+) T(reg) 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 T(reg) cells and to ensure mature T-cell quiescence.
BIO5 Institute, Department of Cell Biology & Anatomy, University of Arizona, Tucson, AZ 85724-5217, USA.
Thomas
T
Doetschman
Allyson
A
Sholl
Hwu dau rw
Hd
Chen
Connie
C
Gard
David A
DA
Hildeman
Ramireddy
R
Bommireddy
D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology; D006529:Hepatomegaly / Q000276:immunology / Q000378:metabolism; D006706:Homeostasis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013163:Splenomegaly / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology
D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta; D019703:Calcineurin; C557393:protein phosphatase 3, catalytic subunit, beta isoform, mouse
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