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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-12, Vol.113 (50), p.E8131-E8131
• Main Authors: Morita, Kaoru, Okamura, Tomohisa, Inoue, Mariko, Komai, Toshihiko, Teruya, Shuzo, Iwasaki, Yukiko, Sumitomo, Shuji, Shoda, Hirofumi, Yamamoto, Kazuhiko, Fujio, Keishi
• Format: Article
• Language: English
• ISSN: 0027-8424
• DOI: 10.1073/pnas.1611286114

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- beta 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- beta 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- beta 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- beta 3-expressing vector. Intriguingly, latent TGF- beta binding protein (Ltbp)3 expression maintained by Egr2 and Egr3 was required for TGF- beta 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- beta 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.