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

R. Bommireddy, O. F. Bueno, J. Martin, I. Ormsby, H. Chen, C. Gard, J. D. Molkentin, G. P. Boivin, G. F. Babcock, T. Doetschman

Research output: Contribution to journalArticle

5 Scopus citations

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 1 2009

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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