title: Coexpression of TIGIT and FCRL3 identifies Helios+ human memory regulatory T cells.
abstract: Two distinct subsets of CD4(+)Foxp3(+) regulatory T (Treg) cells have been described based on the differential expression of Helios, a transcription factor of the Ikaros family. Efforts to understand the origin and biological roles of these Treg populations in regulating immune responses have, however, been hindered by the lack of reliable surface markers to distinguish and isolate them for subsequent functional studies. Using a single-cell cloning strategy coupled with microarray analysis of different Treg functional subsets in humans, we identify the mRNA and protein expression of TIGIT and FCRL3 as a novel surface marker combination that distinguishes Helios(+)FOXP3(+) from Helios(-)FOXP3(+) memory cells. Unlike conventional markers that are modulated on conventional T cells upon activation, we show that the TIGIT/FCRL3 combination allows reliable identification of Helios(+) Treg cells even in highly activated conditions in vitro as well as in PBMCs of autoimmune patients. We also demonstrate that the Helios(-)FOXP3(+) Treg subpopulation harbors a larger proportion of nonsuppressive clones compared with the Helios(+)FOXP3(+) cell subset, which is highly enriched for suppressive clones. Moreover, we find that Helios(-) cells are exclusively responsible for the productions of the inflammatory cytokines IFN-γ, IL-2, and IL-17 in FOXP3(+) cells ex vivo, highlighting important functional differences between Helios(+) and Helios(-) Treg cells. Thus, we identify novel surface markers for the consistent identification and isolation of Helios(+) and Helios(-) memory Treg cells in health and disease, and we further reveal functional differences between these two populations. These new markers should facilitate further elucidation of the functional roles of Helios-based Treg heterogeneity.
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3G 1A4, Canada; Federation of Clinical Immunology Centre of Excellence, Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada;
authors.forename: Khalid
authors.initials: K
authors.lastname: Bin Dhuban
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3G 1A4, Canada; Federation of Clinical Immunology Centre of Excellence, Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada;
authors.forename: Eva
authors.initials: E
authors.lastname: d'Hennezel
authors.affiliation: Division of Allergy and Immunology, McGill University Health Centre, Montreal, Quebec H2C 2P2, Canada;
authors.forename: Emil
authors.initials: E
authors.lastname: Nashi
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec H3A 2B4, Canada;
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Sadiye
authors.initials: S
authors.lastname: Rieder
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Shevach
authors.affiliation: Cancer Biology Research Center, Sanford Research, Sioux Falls, SD 57104.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagata
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3G 1A4, Canada; Federation of Clinical Immunology Centre of Excellence, Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada; Ciro.piccirillo@mcgill.ca.
authors.forename: Ciriaco A
authors.initials: CA
authors.lastname: Piccirillo
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015415:Biomarkers; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D015415:Biomarkers; D016207:Cytokines; C457775:FCRL3 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C111431:IKZF2 protein, human; D011971:Receptors, Immunologic; C534712:TIGIT protein, human; D051740:Ikaros Transcription Factor