Abstract
Autoantibodies induce various autoimmune diseases, including systemic lupus erythematosus (SLE). We previously described that CD4(+)CD25(-)LAG3(+) regulatory T cells (LAG3(+) Treg) are regulated by Egr2, a zinc-finger transcription factor required for the induction of T-cell anergy. We herein demonstrate that LAG3(+) Treg produce high amounts of TGF-β3 in an Egr2- and Fas-dependent manner. LAG3(+) Treg require TGF-β3 to suppress B-cell responses in a murine model of lupus. Moreover, TGF-β3- and LAG3(+) Treg-mediated suppression requires PD-1 expression on B cells. We also show that TGF-β3-expressing human LAG3(+) Treg suppress antibody production and that SLE patients exhibit decreased frequencies of LAG3(+) Treg. These results clarify the mechanism of B-cell regulation and suggest therapeutic strategies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / metabolism
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B-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / cytology*
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Disease Models, Animal
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Early Growth Response Protein 2 / metabolism*
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Female
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Humans
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Immunity, Humoral / immunology*
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Interleukin-2 Receptor alpha Subunit / metabolism
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Lupus Erythematosus, Systemic / metabolism*
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Lymphocyte Activation Gene 3 Protein
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Spleen / metabolism
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T-Lymphocytes, Regulatory / cytology
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Transforming Growth Factor beta3 / metabolism*
Substances
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Antigens, CD
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EGR2 protein, human
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Early Growth Response Protein 2
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Egr2 protein, mouse
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IL2RA protein, human
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Interleukin-2 Receptor alpha Subunit
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TGFB3 protein, human
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Tgfb3 protein, mouse
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Transforming Growth Factor beta3
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Lymphocyte Activation Gene 3 Protein