Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / immunology*
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CD28 Antigens / immunology
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Calcium / metabolism
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Cells, Cultured
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Clonal Anergy / genetics
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Concanavalin A / pharmacology
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Down-Regulation / immunology*
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Drug Combinations
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Immune Sera / pharmacology
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Interferon-gamma / biosynthesis
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / biosynthesis
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Intracellular Fluid / immunology
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Intracellular Fluid / metabolism
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Ionomycin / pharmacology
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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Lymphocyte Subsets / cytology*
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Lymphocyte Subsets / drug effects
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Lymphocyte Subsets / immunology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C3H
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Mice, Knockout
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Mitosis / genetics
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Mitosis / immunology
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Spleen / cytology
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Spleen / immunology
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Spleen / metabolism
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology
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Tetradecanoylphorbol Acetate / pharmacology
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Transforming Growth Factor beta / deficiency
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / physiology*
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Transforming Growth Factor beta1
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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CD28 Antigens
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Drug Combinations
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Immune Sera
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Interleukin-2
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Tgfb1 protein, mouse
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Concanavalin A
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Ionomycin
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Interferon-gamma
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Tetradecanoylphorbol Acetate
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Calcium