Potential role of IL-17-producing CD4/CD8 double negative αβ T cells in psoriatic skin inflammation in a TPA-induced STAT3C transgenic mouse model.
BACKGROUND
Psoriasis is one of the most common immune-mediated chronic inflammatory skin disorders and is accompanied by erythematous scaly plaques. There is growing evidence that the IL-23/Th17 axis plays a critical role in development of the disease. It was recently shown that in addition to CD4+Th17 cells, various IL-17-producing cell subsets such as CD8+Tc17 cells, dermal γδ T cells, and innate lymphoid cells are also involved in the development of psoriatic inflammation in humans.


OBJECTIVE
To investigate which subsets of IL-17-producing cells are involved in psoriasis-like skin inflammation in a TPA (tumor promoter 12-O-tetradecanoylphorbol-13-acetate)-induced K14.Stat3C mouse model.


METHODS
Skin-infiltrating cells were isolated from inflamed lesions of TPA-treated K14.Stat3C transgenic mice, and analyzed for IL-17 producing cell subsets by flow cytometry.


RESULTS
We observed significantly increased numbers of IL-17-producing CD4+T cells, CD8+T cells and dermal γδ T cells in TPA-induced skin lesions of K14.Stat3C mice. Additionally, we found that another IL-17-producing T cell subset, αβ-TCR+CD4CD8 double negative T cells (DN αβ T cells), was also increased in lesional skin. These IL-17-producing DN αβ T cells are NK1.1 negative, suggesting they are not natural killer T cells or mucosal associated invariant T cells. As well as other IL-17-producing cells, DN αβ T cells in the inflamed skin can also respond to IL-23 stimulation to produce IL-17. It is also suggested that DN αβ T cells may express retinoic acid-related orphan receptor gamma t and CC chemokine receptor 6.


CONCLUSIONS
In TPA-induced lesional skin of K14.Stat3C mice, IL-17-producing CD4+Th17 cells, CD8+Tc17 cells, dermal γδ T cells and TCR-cells probably containing ILCs all participated in skin inflammation, which is similar to human clinical psoriatic features. Furthermore, we showed for the first time the possibility that an IL-17-producing DN αβ T cell subset is also involved in psoriatic inflammation.
Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan. Electronic address: azumi.ueyama@shionogi.co.jp.
Azumi
A
Ueyama
Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan.
Chihiro
C
Imura
Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan.
Yasuyuki
Y
Fusamae
Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan.
Kenichiro
K
Tsujii
Shionogi Techno Advance Research Co., Ltd., Toyonaka, Japan.
Yoko
Y
Furue
Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan.
Miwa
M
Aoki
Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan.
Minoru
M
Suzuki
Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan.
Tomohiko
T
Okuda
Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan.
Itsuki
I
Oshima
Global Innovation Office, Shionogi & Co., Ltd., Osaka, Japan.
Kiyoshi
K
Yasui
Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan.
Michitaka
M
Shichijo
Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan.
Mina
M
Yamamoto
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology*; D020381:Interleukin-17 / Q000378:metabolism*; D053760:Interleukin-23 Subunit p19 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D011565:Psoriasis / Q000139:chemically induced / Q000276:immunology*; D054399:Receptors, CCR6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000633:toxicity
C498126:CCR6 protein, mouse; D015704:CD4 Antigens; D016827:CD8 Antigens; C098680:Il17a protein, mouse; C508841:Il23a protein, mouse; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D054399:Receptors, CCR6; C539901:Rorc protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D013755:Tetradecanoylphorbol Acetate
Double negative αβ T cell; IL-17; IL-23; Psoriasis model; Stat3 transgenic mouse; Th17