title: Identification of tonsillar CD4+CD25-LAG3+T cells as naturally occurring IL-10-producing regulatory T cells in human lymphoid tissue.
abstract: IL-10-producing regulatory T cells (IL-10-producing Tregs) are one of the regulatory T cell subsets characterized by the production of high amounts of IL-10, the lack of FOXP3 expression and the strong immunosuppressive capabilities. IL-10-producing Tregs have been primarily reported as induced populations thus far, in part because identifying naturally occurring IL-10-producing Tregs was difficult due to the lack of definitive surface markers. Lymphocyte-activation gene 3 (LAG3) is a CD4 homologue that we have identified as being expressed on IL-10 producing Tregs. In human PBMC, LAG3 combined with CD49b efficiently identifies IL-10-producing Tregs. However, naturally occurring IL-10-producing Tregs in human secondary lymphoid tissue have not been described. In this report, we identified CD4+CD25-LAG3+T cells in human tonsil. This T cell subset produced high amounts of IL-10 and expressed low levels of FOXP3. Surface markers and microarray analysis revealed that this is a distinct tonsillar CD4+T cell subset. CD4+CD25-LAG3+T cells expressed interleukin 10 (IL10), PR/SET domain 1 (PRDM1), and CD274 at high levels and chemokine receptor 5 (CXCR5) at low levels. CD4+CD25-LAG3+T cells suppressed antibody production more efficiently than CD4+CD25+T cells, and CD4+CD25-LAG3+T cells induced B cell apoptosis. Moreover, analysis of humanized mice revealed that this cell subset suppressed a graft-versus-host disease (GVHD) reaction in vivo. Our study reveals the existence of naturally occurring IL-10-producing Tregs in human secondary lymphoid tissue and their function in immune regulation.
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.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: 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; 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: Yumi
authors.initials: Y
authors.lastname: Tsuchida
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: Rika
authors.initials: R
authors.lastname: Kato
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: Department of Otolaryngology, Showa General Hospital, 8-1-1 Hanakoganei, Kodaira-shi, Tokyo 187-8510, Japan.
authors.forename: Asayo
authors.initials: A
authors.lastname: Furukawa
authors.affiliation: Department of Otolaryngology, Showa General Hospital, 8-1-1 Hanakoganei, Kodaira-shi, Tokyo 187-8510, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kitahara
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamasoba
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
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. Electronic address: kfujio-tky@umin.ac.jp.
authors.forename: Keishi
authors.initials: K
authors.lastname: Fujio
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis*; D008221:Lymphoid Tissue / Q000166:cytology*; D051379:Mice; D014066:Palatine Tonsil / Q000166:cytology*; D010641:Phenotype; D000074462:Positive Regulatory Domain I-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D016207:Cytokines; D016753:Interleukin-10; D007371:Interferon-gamma; D000074462:Positive Regulatory Domain I-Binding Factor 1
keywords: IL-10; LAG3; PD-L1; Regulatory T cell