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National Institute of Environmental Health Sciences

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Publication Detail

Title: Calcineurin deficiency decreases inflammatory lesions in transforming growth factor beta1-deficient mice.

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

Published In Clin Exp Immunol, (2009 Dec)

Abstract: Transforming growth factor (TGF) beta1) 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 Abeta (CNAbeta)-deficient mice do not reject allogenic tumours, we have generated Tgfb1(-/-) Cnab(-/-) mice to address whether CNAbeta 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 CNAbeta decreases inflammatory lesions but does not prevent activation of autoreactive T cells. Also Tgfb1(-/-) T cells can undergo activation in the absence of CNAbeta, probably by using the other isoform of calcineurin (CNAalpha) in a compensatory manner. CNAbeta-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.

PubMed ID: 19747209 Exiting the NIEHS site

MeSH Terms: Animals; Autoimmune Diseases/immunology*; Autoimmune Diseases/pathology; Autoimmune Diseases/prevention & control; Calcineurin/deficiency*; Calcineurin/immunology; Cell Differentiation/immunology; Cells, Cultured; Inflammation/immunology*; Inflammation/pathology; Inflammation/prevention & control; Lymphocyte Activation/immunology; Lymphocyte Count; Mice; Mice, Knockout; Spleen/immunology; Survival Analysis; T-Lymphocyte Subsets/immunology; Transforming Growth Factor beta1/immunology*

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Last Reviewed: October 07, 2024