TGF-beta 1 regulates lymphocyte homeostasis by preventing activation and subsequent apoptosis of peripheral lymphocytes.
TGF-beta1 plays an important role in the maintenance of immune homeostasis and self-tolerance. To determine the mechanism by which TGF-beta1 prevents autoimmunity we have analyzed T cell activation in splenic lymphocytes from TGF-beta1-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 Ca(2+) levels. However, upon subsequent stimulation in vitro, increases in Ca(2+) 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 Ca(2+) levels.
Bommireddy
Ramireddy
R
Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Saxena
Vijay
V
Ormsby
Ilona
I
Yin
Moying
M
Boivin
Gregory P
GP
Babcock
George F
GF
Singh
Ram R
RR
Doetschman
Thomas
T
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000235:genetics; D003208:Concanavalin A / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D004338:Drug Combinations; D007106:Immune Sera / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D018106:CD28 Antigens; D004338:Drug Combinations; D007106:Immune Sera; D007376:Interleukin-2; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003208:Concanavalin A; D015759:Ionomycin; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium