Calcineurin deficiency decreases inflammatory lesions in transforming growth factor β1-deficient mice
| Autor: | George F. Babcock, Thomas Doetschman, Ramireddy Bommireddy, Ilona Ormsby, Jennifer H. Martin, Jeffery D. Molkentin, Gregory P. Boivin, C. Gard, H. Chen, Orlando F. Bueno |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
medicine.medical_specialty
medicine.medical_treatment T cell Lymphocyte Immunology Biology Lymphocyte Activation Autoimmune Diseases Transforming Growth Factor beta1 Mice T-Lymphocyte Subsets Lymphocyte homeostasis Internal medicine medicine Animals Immunology and Allergy Lymphocyte Count Cells Cultured Inflammation Mice Knockout Calcineurin Cell Differentiation Animal Models T lymphocyte Survival Analysis Cytokine medicine.anatomical_structure Endocrinology Spleen CD8 Transforming growth factor |
| Zdroj: | Clinical and Experimental Immunology. 158:317-324 |
| ISSN: | 1365-2249 0009-9104 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|