Calcineurin deficiency decreases inflammatory lesions in transforming growth factor β1-deficient mice

R. Bommireddy, O. F. Bueno, J. Martin, I. Ormsby, Hwu Dau Rw Chen, C. Gard, J. D. Molkentin, G. P. Boivin, G. F. Babcock, Thomas C Doetschman

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Transforming growth factor (TGF) β1) is an immunoregulatory cytokine involved in self-tolerance and lymphocyte homeostasis. Tgfb1 knock-out (KO) mice develop severe multi-focal autoimmune inflammatory lesions due to [Ca 2+]i deregulation in T cells, and die within 3 weeks after birth. Because the calcineurin inhibitor FK506 inhibits the hyperresponsiveness of Tgfb1-/- thymocytes, and because calcineurin Aβ (CNAβ)-deficient mice do not reject allogenic tumours, we have generated Tgfb1-/-Cnab-/- mice to address whether CNAβ deficiency prevents T cell activation and inflammation in Tgfb1-/- mice. Here we show that in Tgfb1-/-Cnab-/- mice inflammation is reduced significantly relative to that in Tgfb1-/- mice. However, both CD4+ and CD8+ T cells in double knock-out (DKO) mice are activated, as revealed by up-regulation of CD11a lymphocyte function-associated antigen-1 (LFA-1), CD44 and CD69 and down-regulation of CD62L. These data suggest that deficiency of CNAβ decreases inflammatory lesions but does not prevent activation of autoreactive T cells. Also Tgfb1-/- T cells can undergo activation in the absence of CNAβ, probably by using the other isoform of calcineurin (CNAα) in a compensatory manner. CNAβ-deficient T cells undergo spontaneous activation in vivo and are activated upon anti-T cell receptor stimulation in vitro. Understanding the role of calcineurin in T cell regulation should open up new therapeutic opportunities for inflammation and cancer.

Original languageEnglish (US)
Pages (from-to)317-324
Number of pages8
JournalClinical and Experimental Immunology
Volume158
Issue number3
DOIs
StatePublished - Dec 2009

Fingerprint

Calcineurin
Transforming Growth Factors
T-Lymphocytes
Inflammation
Knockout Mice
Self Tolerance
Lymphocyte Function-Associated Antigen-1
Tacrolimus
Thymocytes
T-Cell Antigen Receptor
Neoplasms
Protein Isoforms
Homeostasis
Up-Regulation
Down-Regulation
Parturition
Lymphocytes
Cytokines

Keywords

  • Autoimmunity
  • CNAβ
  • Inflammation
  • Knockout
  • T cells
  • TGFβ1

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Calcineurin deficiency decreases inflammatory lesions in transforming growth factor β1-deficient mice. / Bommireddy, R.; Bueno, O. F.; Martin, J.; Ormsby, I.; Chen, Hwu Dau Rw; Gard, C.; Molkentin, J. D.; Boivin, G. P.; Babcock, G. F.; Doetschman, Thomas C.

In: Clinical and Experimental Immunology, Vol. 158, No. 3, 12.2009, p. 317-324.

Research output: Contribution to journalArticle

Bommireddy, R. ; Bueno, O. F. ; Martin, J. ; Ormsby, I. ; Chen, Hwu Dau Rw ; Gard, C. ; Molkentin, J. D. ; Boivin, G. P. ; Babcock, G. F. ; Doetschman, Thomas C. / Calcineurin deficiency decreases inflammatory lesions in transforming growth factor β1-deficient mice. In: Clinical and Experimental Immunology. 2009 ; Vol. 158, No. 3. pp. 317-324.
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