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1 Regulates Lymphocyte Homeostasis by Preventing Activation and Subsequent Apoptosis of Peripheral Lymphocytes1
,¶
Departments of
*
Molecular Genetics, Biochemistry and Microbiology,
Internal Medicine,
Pathology and Laboratory Medicine, and
Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and
¶ Shriners Hospital for Children, Cincinnati, OH 45229
TGF-
1 plays an important role in the maintenance of immune homeostasis and self-tolerance. To determine the mechanism by which TGF-1 prevents autoimmunity we have analyzed T cell activation in splenic lymphocytes from TGF-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-
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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