Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis.
Th1 and Th17 T cells are often colocalized in pathological environments, yet Th1-derived IFN-gamma inhibits Th17 cell development in vitro. We explored the physiologic basis of this paradox in humans. In this study, we demonstrate increased the number of CD4(+) and CD8(+) IL-17(+) T cells in skin lesions of psoriasis. Furthermore, we show that myeloid APCs potently support induction of IL-17(+) T cells, and that this activity is greatly increased in psoriasis. We tested stimuli that might account for this activity. Th1 cells and IFN-gamma are increased in psoriatic blood and lesional skin. We show that IFN-gamma programs myeloid APCs to induce human IL-17(+) T cells via IL-1 and IL-23. IFN-gamma also stimulates APC production of CCL20, supporting migration of IL-17(+) T cells, and synergizes with IL-17 in the production of human beta-defensin 2, an antimicrobial and chemotactic protein highly overexpressed by psoriatic keratinocytes. This study reveals a novel mechanistic interaction between Th1 and IL-17(+) T cells, challenges the view that Th1 cells suppress Th17 development through IFN-gamma, and suggests that Th1 and IL-17(+) T cells may collaboratively contribute to human autoimmune diseases.
Kryczek
Ilona
I
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Bruce
Allen T
AT
Gudjonsson
Johann E
JE
Johnston
Andrew
A
Aphale
Abhishek
A
Vatan
Linhua
L
Szeliga
Wojciech
W
Wang
Yin
Y
Liu
Yan
Y
Welling
Theodore H
TH
Elder
James T
JT
Zou
Weiping
W
D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000502:physiology*; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011565:Psoriasis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D020381:Interleukin-17; D007371:Interferon-gamma
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