title: CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner.
abstract: Treg cells are critical for the prevention of autoimmune diseases and are thus prime candidates for cell-based clinical therapy. However, human Treg cells are "plastic", and are able to produce IL-17 under inflammatory conditions. Here, we identify and characterize the human Treg subpopulation that can be induced to produce IL-17 and identify its mechanisms. We confirm that a subpopulation of human Treg cells produces IL-17 in vitro when activated in the presence of IL-1β, but not IL-6. "IL-17 potential" is restricted to population III (CD4(+) CD25(hi) CD127(lo) CD45RA(-) ) Treg cells expressing the natural killer cell marker CD161. We show that these cells are functionally as suppressive and have similar phenotypic/molecular characteristics to other subpopulations of Treg cells and retain their suppressive function following IL-17 induction. Importantly, we find that IL-17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL-17. Finally, we show that CD161(+) population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL-17-producing Treg-cell population at these sites. As IL-17 production from this Treg-cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary.
authors.affiliation: Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK. susan.john@kcl.ac.uk
authors.forename: Behdad
authors.initials: B
authors.lastname: Afzali
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mitchell
authors.forename: Francis C
authors.initials: FC
authors.lastname: Edozie
authors.forename: Giovanni A M
authors.initials: GA
authors.lastname: Povoleri
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Dowson
authors.forename: Laura
authors.initials: L
authors.lastname: Demandt
authors.forename: Gina
authors.initials: G
authors.lastname: Walter
authors.forename: James B
authors.initials: JB
authors.lastname: Canavan
authors.forename: Cristiano
authors.initials: C
authors.lastname: Scotta
authors.forename: Bina
authors.initials: B
authors.lastname: Menon
authors.forename: Prabhjoat S
authors.initials: PS
authors.lastname: Chana
authors.forename: Wafa
authors.initials: W
authors.lastname: Khamri
authors.forename: Shahram Y
authors.initials: SY
authors.lastname: Kordasti
authors.forename: Susanne
authors.initials: S
authors.lastname: Heck
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.forename: Timothy
authors.initials: T
authors.lastname: Tree
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Cope
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Taams
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lechler
authors.forename: Susan
authors.initials: S
authors.lastname: John
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D000328:Adult; D000368:Aged; D015704:CD4 Antigens / Q000096:biosynthesis; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D015850:Interleukin-6 / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000276:immunology / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D053583:Interleukin-1beta; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D053699:Interleukin-7 Receptor alpha Subunit; D055651:NK Cell Lectin-Like Receptor Subfamily B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D017493:Leukocyte Common Antigens
keywords: Conversion; Human; Regulatory T (Treg) cells; STAT3; Th17