title: Identification of IL-17-producing FOXP3+ regulatory T cells in humans.
abstract: IL-17-producing CD4(+) T helper (Th17) cells have recently been defined as a unique subset of proinflammatory helper cells whose development depends on signaling initiated by IL-6 and TGF-beta, autocrine activity of IL-21, activation of STAT3, and induction of the orphan nuclear receptor RORgammat. The maintenance, expansion, and further differentiation of the committed Th17 cells depend on IL-1beta and IL-23. IL-17 was originally found produced by circulating human CD45RO(+) memory T cells. A recent study found that human Th17 memory cells selectively express high levels of CCR6. In this study, we report that human peripheral blood and lymphoid tissue contain a significant number of CD4(+)FOXP3(+) T cells that express CCR6 and have the capacity to produce IL-17 upon activation. These cells coexpress FOXP3 and RORgammat transcription factors. The CD4(+)FOXP3(+)CCR6(+) IL-17-producing cells strongly inhibit the proliferation of CD4(+) responder T cells. CD4(+)CD25(high)-derived T-cell clones express FOXP3, RORgammat, and IL-17 and maintain their suppressive function via a cell-cell contact mechanism. We further show that human CD4(+)FOXP3(+)CCR6(-) regulatory T (Treg) cells differentiate into IL-17 producer cells upon T-cell receptor stimulation in the presence of IL-1beta, IL-2, IL-21, IL-23, and human serum. This, together with the finding that human thymus does not contain IL-17-producing Treg cells, suggests that the IL-17(+)FOXP3(+) Treg cells are generated in the periphery. IL-17-producing Treg cells may play critical roles in antimicrobial defense, while controlling autoimmunity and inflammation.
authors.affiliation: Department of Immunology, Center for Cancer Immunology Research, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kui Shin
authors.initials: KS
authors.lastname: Voo
authors.forename: Yui-Hsi
authors.initials: YH
authors.lastname: Wang
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Santori
authors.forename: Cesar
authors.initials: C
authors.lastname: Boggiano
authors.forename: Yi-Hong
authors.initials: YH
authors.lastname: Wang
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Arima
authors.forename: Laura
authors.initials: L
authors.lastname: Bover
authors.forename: Shino
authors.initials: S
authors.lastname: Hanabuchi
authors.forename: Jahan
authors.initials: J
authors.lastname: Khalili
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Marinova
authors.forename: Biao
authors.initials: B
authors.lastname: Zheng
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
mesh_terms: D002999:Clone Cells; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D053759:Interleukin-23 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D014066:Palatine Tonsil / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018168:Receptors, Retinoic Acid / Q000276:immunology; D011988:Receptors, Thyroid Hormone / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053759:Interleukin-23; D015850:Interleukin-6; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D000098546:Interleukin-21