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Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-?3 production.


ABSTRACT: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by multiorgan inflammation induced by autoantibodies. Early growth response gene 2 (Egr2), a transcription factor essential for T-cell anergy induction, controls systemic autoimmunity in mice and humans. We have previously identified a subpopulation of CD4+ regulatory T cells, CD4+CD25-LAG3+ cells, that characteristically express both Egr2 and LAG3 and control mice model of lupus via TGF-?3 production. However, due to the mild phenotype of lymphocyte-specific Egr2-deficient mice, the presence of an additional regulator has been speculated. Here, we show that Egr2 and Egr3 expressed in T cells cooperatively prevent humoral immune responses by supporting TGF-?3 secretion. T cell-specific Egr2/Egr3 double-deficient (Egr2/3DKO) mice spontaneously developed an early onset lupus-like disease that was more severe than in T cell-specific Egr2-deficient mice. In accordance with the observation that CD4+CD25-LAG3+ cells from Egr2/3DKO mice completely lost the capacity to produce TGF-?3, the excessive germinal center reaction in Egr2/3DKO mice was suppressed by the adoptive transfer of WT CD4+CD25-LAG3+ cells or treatment with a TGF-?3-expressing vector. Intriguingly, latent TGF-? binding protein (Ltbp)3 expression maintained by Egr2 and Egr3 was required for TGF-?3 production from CD4+CD25-LAG3+ cells. Because Egr2 and Egr3 did not demonstrate cell intrinsic suppression of the development of follicular helper T cells, Egr2- and Egr3-dependent TGF-?3 production by CD4+CD25-LAG3+ cells is critical for controlling excessive B-cell responses. The unique attributes of Egr2/Egr3 in T cells may provide an opportunity for developing novel therapeutics for autoantibody-mediated diseases including SLE.

SUBMITTER: Morita K 

PROVIDER: S-EPMC5167141 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-β3 production.

Morita Kaoru K   Okamura Tomohisa T   Inoue Mariko M   Komai Toshihiko T   Teruya Shuzo S   Iwasaki Yukiko Y   Sumitomo Shuji S   Shoda Hirofumi H   Yamamoto Kazuhiko K   Fujio Keishi K  

Proceedings of the National Academy of Sciences of the United States of America 20161130 50


Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by multiorgan inflammation induced by autoantibodies. Early growth response gene 2 (Egr2), a transcription factor essential for T-cell anergy induction, controls systemic autoimmunity in mice and humans. We have previously identified a subpopulation of CD4<sup>+</sup> regulatory T cells, CD4<sup>+</sup>CD25<sup>-</sup>LAG3<sup>+</sup> cells, that characteristically express both Egr2 and LAG3 and control mice mo  ...[more]

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