Divergent effects of calcineurin Aβ on regulatory and conventional T-cell homeostasis

Thomas C Doetschman, Allyson Sholl, Hwu Dau Rw Chen, Connie Gard, David A. Hildeman, Ramireddy Bommireddy

Research output: Contribution to journalArticle

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Abstract

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+ Treg 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+ Treg 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 Treg cells and to ensure mature T-cell quiescence.

Original languageEnglish (US)
Pages (from-to)321-330
Number of pages10
JournalClinical Immunology
Volume138
Issue number3
DOIs
StatePublished - Mar 2011

Fingerprint

Calcineurin
Regulatory T-Lymphocytes
Homeostasis
T-Lymphocytes
Catalytic Domain
Tacrolimus
NFATC Transcription Factors
Hepatomegaly
Splenomegaly
Graft Rejection
Thymocytes
Phosphoric Monoester Hydrolases
Interleukin-4
Cyclosporine
Interleukin-6
Maintenance
Cytokines

Keywords

  • Calcineurin
  • Cyclosporin A
  • FOXP3
  • Inflammation
  • Knockout
  • Treg cells

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Divergent effects of calcineurin Aβ on regulatory and conventional T-cell homeostasis. / Doetschman, Thomas C; Sholl, Allyson; Chen, Hwu Dau Rw; Gard, Connie; Hildeman, David A.; Bommireddy, Ramireddy.

In: Clinical Immunology, Vol. 138, No. 3, 03.2011, p. 321-330.

Research output: Contribution to journalArticle

Doetschman, Thomas C ; Sholl, Allyson ; Chen, Hwu Dau Rw ; Gard, Connie ; Hildeman, David A. ; Bommireddy, Ramireddy. / Divergent effects of calcineurin Aβ on regulatory and conventional T-cell homeostasis. In: Clinical Immunology. 2011 ; Vol. 138, No. 3. pp. 321-330.
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