Induction of IL-17+ T Cell Trafficking and Development by IFN-γ: Mechanism and Pathological Relevance in Psoriasis

Kryczek, Ilona; Bruce, Allen T.; Guðjónsson, Jóhann E.; Johnston, Andrew; Aphale, Abhishek; Vatan, Linhua; Szeliga, Wojciech; Wang, Yin; Liu, Yan; Welling, Theodore H.; Elder, James T.; Zou, Weiping

doi:10.4049/jimmunol.181.7.4733

Cited by 417 publications

(393 citation statements)

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“…Interestingly, in addition to Th17 cells, increases in IL-17 + CD8 + T cells and IL-17 + γδ T cells also were detected in both skin and DLNs of K14cre; Dlx3 Kin/f mice. These results are consistent with recent reports demonstrating that IL-17 can be produced by IL-17 + CD8 + T cells and γδ T cells, as well as by Th 17 cells (31,33). The absolute numbers for each subpopulation are presented in Fig.…”

Section: Il-17-expressing T Cells and Leukocytes Are Increased In Thesupporting

confidence: 82%

“…2C). In addition to Th17 cells, other sources of IL-17, including CD8 + T cells and γδ T cells, have been reported in skin inflammatory responses (31,32). To evaluate IL-17a-expressing cells in skin and draining lymph nodes (DLNs) of WT and K14cre;Dlx3 Kin/f mice, we performed analytical flow cytometry for CD4 + T cells, CD8 + T cells, and γδ T cells and then analyzed intracellular IL-17a expression in each of these gated cell populations ( Fig.…”

Section: Il-17-expressing T Cells and Leukocytes Are Increased In Thementioning

confidence: 99%

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Epidermal ablation of Dlx3 is linked to IL-17–associated skin inflammation

Hwang

Kita

Kwon

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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In an effort to understand the role of Distal-less 3 (Dlx3) in cutaneous biology and pathophysiology, we generated and characterized a mouse model with epidermal ablation of Dlx3. K14cre;Dlx3 Kin/f mice exhibited epidermal hyperproliferation and abnormal differentiation of keratinocytes. Results from subsequent analyses revealed cutaneous inflammation that featured accumulation of IL-17-producing CD4 + T, CD8 + T, and γδ T cells in the skin and lymph nodes of K14cre;Dlx3 Kin/f mice. The gene expression signature of K14cre;Dlx3 Kin/f skin shared features with lesional psoriatic skin, and Dlx3 expression was markedly and selectively decreased in psoriatic skin. Interestingly, cultured Dlx3 null keratinocytes triggered cytokine production that is potentially linked to inflammatory responses in K14cre;Dlx3 Kin/f mice. Thus, Dlx3 ablation in epidermis is linked to altered epidermal differentiation, barrier development, and IL-17-associated skin inflammation. This model provides a platform that will allow the systematic exploration of the contributions of keratinocytes to cutaneous inflammation.barrier function | psoriasis | inflammatory diseases | homeobox transcription factor | mouse model

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Section: Il-17-expressing T Cells and Leukocytes Are Increased In Thesupporting

confidence: 82%

Section: Il-17-expressing T Cells and Leukocytes Are Increased In Thementioning

confidence: 99%

Epidermal ablation of Dlx3 is linked to IL-17–associated skin inflammation

Hwang

Kita

Kwon

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…2F) and CD14 1 (Fig. 2I) [4][5][6][7][8][9][10][11][12][13][14][15][16]. The local detection of CD8 1 IL-17 1 cells is of particular interest since a noncytotoxic 17 (Tc17) CD27 1/À CD28 1 CD45RA À subset has recently been described in other inflammatory diseases [17].…”

Section: Resultsmentioning

confidence: 99%

“…In addition to the previously described roles of Th1 clones and the critical effector cytokine IFN-g in ML pathogenesis [5], these cells are involved in Th17 recruitment to tissue lesions. For example, the recruitment of Th17 cells is stimulated by a Th1 clone in psoriatic lesions [13]. In this circumstance, Th1 and Th17 cells act together to induce immune-mediated tissue damage.…”

mentioning

confidence: 99%

Human mucosal leishmaniasis: Neutrophils infiltrate areas of tissue damage that express high levels of Th17‐related cytokines

et al. 2010

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Mucosal leishmaniasis (ML) is characterised by severe tissue destruction. Herein, we evaluated the involvement of the IL-17-type response in the inflammatory infiltrate of biopsy specimens from 17 ML patients. IL-17 and IL-17-inducing cytokines (IL-1b, IL-23, IL-6 and TGF-b) were detected by immunohistochemistry in ML patients. IL-17 1 cells exhibited CD4 1 , CD8 1 or CD14 1 phenotypes, and numerous IL-17 1 cells co-expressed the CC chemokine receptor 6 (CCR6). Neutrophils, a hallmark of Th17-mediated inflammation, were regularly detected in necrotic and perinecrotic areas and stained positive for neutrophil elastase, myeloperoxidase and MMP-9. Taken together, these observations demonstrate the existence of Th17 cells in ML lesions associated with neutrophils in areas of tissue injury and suggest that IL-17 is involved in ML pathogenesis.Key words: Human . Mucosal leishmaniasis . Neutrophils . Th17 IntroductionMucosal leishmaniasis (ML), a severe chronic disease caused by leishmania protozoa, remains a serious health problem in several parts of the world, including Brazil [1]. ML is at the hyperresponsive end of the spectrum of clinical diseases caused by Leishmania braziliensis [1]. Uncontrolled immune responses have been implicated in ML pathogenesis because T lymphocytes from ML patients initiate intense responses (characterised by lymphoproliferation and cytokine production) despite the low number of parasites in mucosal lesions [2][3][4]. In addition to Th1 cytokines, TGF-b and IL-6 are also produced in ML lesions, but the significance of this finding is poorly understood [5].Th17 cells participate in inflammatory responses to several human infectious agents [6,7]. IL-17, the Th17 signature cytokine, induces tissue damage mediated by neutrophil attraction and proteinase release. Neutrophil recruitment mediated by IL-17 1 cells contributes to disease progression in susceptible mouse strains infected with L. major [8]. Although the cytokine combination that leads to human Th17 differentiation and maintenance remains controversial, TGF-b and IL-6, along with IL-23 and IL-1b, have been implicated in this phenomenon [9,10].Recently in human ML, IL-17 expression has been detected determined. In this study, we expand on the observations reported by Bacellar et al. [11] by demonstrating that in addition to Th17 cells, CD8 1 and CD14 1 cells express IL-17. We also detected the presence of neutrophils expressing proteinases in tissue-damaged areas, suggesting a potential function for Th17 cells in ML lesions. Results and discussionExpression of IL-17, Th17-inducing cytokines and retinoic acid-related orphan receptor ct (RORrt) IL-17 expression was consistently higher in ML lesions (n 5 12) than in normal mucosal samples (n 5 4), as shown in Fig. 1A and B. Marked expression was detected in mononuclear cells, endothelial cells and perivascular fusiform cells. No reactivity was detected using an isotype control antibody (Fig. 1G). As for cytokines involved in IL-17 production, ML lesions presented an intense expressio...

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“…2A, B). We further examined multiple chemokine receptors and intergrin molecules which are associated with Treg 10,11 and Th17 cell 12,13 tissue trafficking in humans, including CCR4, CCR5, CCR6, CXCR4, CD161, CD49D, and CD49F. IL-8 C Foxp3 C and IL-8 ¡ Foxp3 C Treg cells expressed similar levels of these molecules.…”

Section: Foxp3mentioning

confidence: 99%