title: Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans.
abstract: CD4(+) regulatory T (Treg) cells expressing CD25 and the transcription factor forkhead box P3 (FOXP3) are indispensable for immunological self-tolerance and homeostasis. FOXP3(+)CD25(+)CD4(+) T cells in humans, however, are heterogeneous in function and differentiation status, including suppressive or nonsuppressive cells as well as resting or activated Treg cells. We have searched for cell surface markers specific for suppression-competent Treg cells by using a panel of currently available monoclonal antibodies reactive with human T cells. We found that CD15s (sialyl Lewis x) was highly specific for activated, terminally differentiated, and most suppressive FOXP3(high) effector Treg (eTreg) cells and able to differentiate them in various clinical settings from nonsuppressive FOXP3(+) T cells secreting inflammatory cytokines. For example, CD15s(+)FOXP3(+) eTreg cells were increased in sarcoidosis, whereas it was nonsuppressive CD15s(-)FOXP3(+) T cells that were expanded in lupus flares. FOXP3(+) cells induced from conventional CD4(+) T cells by T-cell receptor stimulation hardly expressed CD15s. CD15s(+)CD4(+) T-cell depletion was sufficient to evoke and enhance in vitro immune responses against tumor or viral antigens. Collectively, we have identified CD15s as a biomarker instrumental in both phenotypic and functional analysis of FOXP3(+)CD4(+) T-cell subpopulations in health and disease. It allows specific targeting of eTreg cells, rather than whole FOXP3(+)CD4(+) T cells, in controlling immune responses.
authors.affiliation: INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI), 75013 Paris, France; Assistance Publique - Hôpitaux de Paris (AP-HP), Département d'Immunologie, Hôpital Pitié-Salpêtrière, 75013 Paris, France; shimon@ifrec.osaka-u.ac.jp makoto.miyara@psl.aphp.fr guy.gorochov@upmc.fr.
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyara
authors.affiliation: INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI), 75013 Paris, France; Assistance Publique - Hôpitaux de Paris (AP-HP), Département d'Immunologie, Hôpital Pitié-Salpêtrière, 75013 Paris, France;
authors.forename: Driss
authors.initials: D
authors.lastname: Chader
authors.affiliation: Département de Chirurgie Thoracique et de Transplantation Pulmonaire, Hôpital Foch, 92151 Suresnes, France;
authors.forename: Edouard
authors.initials: E
authors.lastname: Sage
authors.affiliation: Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan;
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sugiyama
authors.affiliation: Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan;
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nishikawa
authors.affiliation: AP-HP, Service de Pneumologie, Hôpital Avicenne, 93000 Bobigny, France;
authors.forename: Diane
authors.initials: D
authors.lastname: Bouvry
authors.affiliation: INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI), 75013 Paris, France; Assistance Publique - Hôpitaux de Paris (AP-HP), Département d'Immunologie, Hôpital Pitié-Salpêtrière, 75013 Paris, France;
authors.forename: Laetitia
authors.initials: L
authors.lastname: Claër
authors.affiliation: Becton-Dickinson, San Diego, CA 92121;
authors.forename: Ravi
authors.initials: R
authors.lastname: Hingorani
authors.affiliation: Becton-Dickinson, San Diego, CA 92121;
authors.forename: Robert
authors.initials: R
authors.lastname: Balderas
authors.affiliation: Becton-Dickinson, San Diego, CA 92121;
authors.forename: Jurg
authors.initials: J
authors.lastname: Rohrer
authors.affiliation: Becton-Dickinson, San Diego, CA 92121;
authors.forename: Noel
authors.initials: N
authors.lastname: Warner
authors.affiliation: Département de Chirurgie Thoracique et de Transplantation Pulmonaire, Hôpital Foch, 92151 Suresnes, France;
authors.forename: Alain
authors.initials: A
authors.lastname: Chapelier
authors.affiliation: AP-HP, Service de Pneumologie, Hôpital Avicenne, 93000 Bobigny, France;
authors.forename: Dominique
authors.initials: D
authors.lastname: Valeyre
authors.affiliation: Research Complex for Medical Frontiers, Aichi Medical University, Yazako, Nagakute 480-1195, Japan;
authors.forename: Reiji
authors.initials: R
authors.lastname: Kannagi
authors.affiliation: Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan; shimon@ifrec.osaka-u.ac.jp makoto.miyara@psl.aphp.fr guy.gorochov@upmc.fr.
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.affiliation: INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI), 75013 Paris, France; AP-HP, Service de Médecine Interne 2, Institut E3M, Centre National de Référence des Maladies Auto-Immune et Systémiques Rares, Hôpital Pitié-Salpêtrière, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI), 75013 Paris, France.
authors.forename: Zahir
authors.initials: Z
authors.lastname: Amoura
authors.affiliation: INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI), 75013 Paris, France; Assistance Publique - Hôpitaux de Paris (AP-HP), Département d'Immunologie, Hôpital Pitié-Salpêtrière, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI), 75013 Paris, France shimon@ifrec.osaka-u.ac.jp makoto.miyara@psl.aphp.fr guy.gorochov@upmc.fr.
authors.forename: Guy
authors.initials: G
authors.lastname: Gorochov
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016256:Lewis X Antigen / Q000276:immunology*; D000080506:Sialyl Lewis X Antigen; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018836:Inflammation Mediators; D016256:Lewis X Antigen; D000080506:Sialyl Lewis X Antigen
keywords: CD15s; FOXP3; autoimmunity; regulatory T cells; tumor immunity