TGF-β1 regulates lymphocyte homeostasis by preventing activation and subsequent apoptosis of peripheral lymphocytes

Ramireddy Bommireddy, Vijay Saxena, Ilona Ormsby, Moying Yin, Gregory P. Boivin, George F. Babcock, Ram R. Singh, Thomas Doetschman

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

TGF-β1 plays an important role in the maintenance of immune homeostasis and self-tolerance. To determine the mechanism by which TGF-β1 prevents autoimmunity we have analyzed T cell activation in splenic lymphocytes from TGF-β1 -deficient mice. Here we demonstrate that unlike wild-type splenic lymphocytes, those from Tgfb1-/- mice are hyporesponsive to receptor-mediated mitogenic stimulation, as evidenced by diminished proliferation and reduced IL-2 production. However, they have elevated levels of IFN-γ and eventually undergo apoptosis. Receptor-independent stimulation of Tgfb1-/- T cells by PMA plus ionomycin induces IL-2 production and mitogenic response, and it rescues them from anergy. Tgfb1-/- T cells display decreased CD3 expression; increased expression of the activation markers LFA-1, CD69, and CD122; and increased cell size, all of which indicate prior activation. Consistently, mutant CD4+ T cells have elevated intracellular Ca2+ levels. However, upon subsequent stimulation in vitro, increases in Ca2+ levels are less than those in wild-type cells. This is also consistent with the anergic phenotype. Together, these results demonstrate that the ex vivo proliferative hyporesponsiveness of Tgfb1-/- splenic lymphocytes is due to prior in vivo activation of T cells resulting from deregulated intracellular Ca2+ levels.

Original languageEnglish (US)
Pages (from-to)4612-4622
Number of pages11
JournalJournal of Immunology
Volume170
Issue number9
StatePublished - May 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Bommireddy, R., Saxena, V., Ormsby, I., Yin, M., Boivin, G. P., Babcock, G. F., Singh, R. R., & Doetschman, T. (2003). TGF-β1 regulates lymphocyte homeostasis by preventing activation and subsequent apoptosis of peripheral lymphocytes. Journal of Immunology, 170(9), 4612-4622.