Identification of IL-17-producing FOXP3+ regulatory T cells in humans.
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.
Voo
Kui Shin
KS
Department of Immunology, Center for Cancer Immunology Research, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
Wang
Yui-Hsi
YH
Santori
Fabio R
FR
Boggiano
Cesar
C
Wang
Yi-Hong
YH
Arima
Kazuhiko
K
Bover
Laura
L
Hanabuchi
Shino
S
Khalili
Jahan
J
Marinova
Ekaterina
E
Zheng
Biao
B
Littman
Dan R
DR
Liu
Yong-Jun
YJ
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
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