title: TGF-β3-expressing CD4+CD25(-)LAG3+ regulatory T cells control humoral immune responses.
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.
authors.affiliation: 1] Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan [2] Max Planck-The University of Tokyo Center for Integrative Inflammology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Okamura
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Shuji
authors.identifier: 0000000349802664
authors.initials: S
authors.lastname: Sumitomo
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Morita
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Iwasaki
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakachi
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Komai
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Shoda
authors.affiliation: Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Miyazaki
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Fujio
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D004195:Disease Models, Animal; D051767:Early Growth Response Protein 2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D053782:Transforming Growth Factor beta3 / Q000378:metabolism*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; C497326:EGR2 protein, human; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; C509044:TGFB3 protein, human; C509045:Tgfb3 protein, mouse; D053782:Transforming Growth Factor beta3; D000093322:Lymphocyte Activation Gene 3 Protein