Inflammatory effects of ex vivo human Th17 cells are suppressed by regulatory T cells.
Th17 cells are proinflammatory cells associated with many immune-mediated diseases. Major factors limiting the study of human Th17 cells are the lack of an accepted method for their in vitro differentiation or for isolation of a homogenous population of Th17 cells that do not cosecrete IFN-gamma. To overcome these hurdles, we established a novel method to isolate in vivo differentiated Th17 cells from peripheral blood by sorting CD161(+)CCR4(+)CCR6(+)CXCR3(-)CD4(+) T cells. The resulting cells produce high levels of IL-17 but not IFN-gamma, express high levels of retinoic acid-related orphan receptor variant 2, and maintain this phenotype upon expansion. Ex vivo Th17 cells exhibit a low cytotoxic potential and are hyporesponsive to polyclonal anti-CD3/anti-CD28 stimulation. Importantly, ex vivo Th17 cells were susceptible to suppression by both naive and memory regulatory T cells (Tregs), which inhibited production of IL-17, IL-22, and CXCL8. Moreover, Tregs suppressed the antifibrotic effects of Th17 cells in a wound-healing model. These findings provide new tools for the study of normal and pathological functions of bona fide Th17 cells in humans. They also provide new insight into the cross-talk between Th17 cells and immune and nonimmune cells, and they establish the paradigm that adoptive Treg-based therapies may effectively limit Th17-mediated inflammation.
Crome
Sarah Q
SQ
Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
Clive
Breanna
B
Wang
Adele Y
AY
Kang
Christine Y
CY
Chow
Vickie
V
Yu
Jie
J
Lai
Amy
A
Ghahary
Aziz
A
Broady
Raewyn
R
Levings
Megan K
MK
D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation / Q000276:immunology*; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D016130:Immunophenotyping; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000502:physiology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000276:immunology; D000097043:Interleukin-22
D018836:Inflammation Mediators; D020381:Interleukin-17; D016209:Interleukin-8; D007378:Interleukins; D000097043:Interleukin-22; C508606:CXCL8 protein, human