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The Journal of Immunology, 2003, 170: 4612-4622.
Copyright © 2003 by The American Association of Immunologists

TGF-{beta}1 Regulates Lymphocyte Homeostasis by Preventing Activation and Subsequent Apoptosis of Peripheral Lymphocytes1

Ramireddy Bommireddy*, Vijay Saxena{dagger}, Ilona Ormsby*, Moying Yin*, Gregory P. Boivin{ddagger}, George F. Babcock§,¶, Ram R. Singh{dagger} and Thomas Doetschman2,*

Departments of * Molecular Genetics, Biochemistry and Microbiology, {dagger} Internal Medicine, {ddagger} Pathology and Laboratory Medicine, and § Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and Shriners Hospital for Children, Cincinnati, OH 45229

TGF-{beta}1 plays an important role in the maintenance of immune homeostasis and self-tolerance. To determine the mechanism by which TGF-{beta}1 prevents autoimmunity we have analyzed T cell activation in splenic lymphocytes from TGF-{beta}1-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-{gamma} 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.




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