Th1 and Th17 T cells are often colocalized in pathological environments, yet Th1-derived IFN-γ 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-γ are increased in psoriatic blood and lesional skin. We show that IFN-γ programs myeloid APCs to induce human IL-17+ T cells via IL-1 and IL-23. IFN-γ also stimulates APC production of CCL20, supporting migration of IL-17+ T cells, and synergizes with IL-17 in the production of human β-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-γ, and suggests that Th1 and IL-17+ T cells may collaboratively contribute to human autoimmune diseases.
Studies show that CD4+ IL-17+ T cells (Th17) and IL-17 play an active role in inflammation and autoimmune diseases in murine systems (1, 2, 3, 4, 5, 6, 7, 8, 9). Although Th17 and CD8+ IL-17+ T cells were found in both mouse and human tumors (10, 11), CD8+ IL-17+ T cells have not been described as increased in human autoimmune diseases. In mice, the cytokine mixture of TGFβ and IL-6 promotes differentiation of Th17 (12, 13, 14) and CD8+ IL-17+ T cells (10, 11), but in humans, TGFβ or this combination of cytokines is thought to suppress Th17 cell differentiation from naive T cells (15, 16). The cytokines IL-1 and IL-23 are important for amplifying and stabilizing Th17 cell differentiation from naive T cells in mice (2, 4, 5, 6, 11, 17, 18, 19, 20, 21) and in humans (16). However, it remains poorly understood which factors promote IL-23 production in humans and control the development and trafficking of human IL-17+ T cells (22). Furthermore, Th1 cells are reported to inhibit Th17 development through IFN-γ (12, 13, 14). Why, then, are Th1 and Th17 cells often colocalized in pathological environments (1, 2, 3, 4, 5, 6, 7, 8, 9, 23, 24), and what is the mechanism and pathological relevance of this colocalization?
To address these questions, we studied psoriasis, a common, chronic disease of the skin and joints mediated by T cell interactions with keratinocytes and other skin cells. Previous studies implicated Th1 cells and the Th1 promoting cytokine, IL-12, in psoriasis pathogenesis and maintenance (23, 24, 25, 26). However, polymorphisms in IL-12p40 and the IL-23R, but not the IL-12R, have been associated with psoriasis (27, 28). Furthermore, an Ab that neutralizes IL-12p40, and thereby both IL-23 and IL-12, has potent effects in treating psoriasis (29). Recently, CD4+ IL-17+ T cells (Th17) have been isolated from psoriatic plaques (16, 24, 30). However, the relative number of Th17 cells in these lesions remains unquantified, and the proportion of CD8+ IL-17+ T cells is unknown. Furthermore, it has been reported that blocking IL-23 has no effects on Th17 cell development mediated by myeloid APCs in humans (15), whereas another study suggested that APC-derived IL-23 was associated with Th17 cell development in psoriasis (16). However, it has not been experimentally demonstrated whether psoriatic APC subsets induce IL-17+ T cells, and whether psoriatic APC-induced Th17 cells are mechanistically due to IL-23 or other cytokines.
In the current investigation, we explored the phenotype and function of IL-17-secreting T cells in psoriatic and healthy skin, and the factors supporting their trafficking to and induction in lesional skin. Specifically, we show that IFN-γ is demonstrated as a potent promoter of IL-17+ T cell trafficking, induction, and function. Our observations support a model wherein Th1 and IL-17+ T cells mechanistically interact and collaboratively contribute to human autoimmune disease pathogenesis.
Materials and Methods
All subjects provided written, informed consent. PBMC and skin biopsy samples were obtained from healthy donors and patients with psoriasis. Before biopsy, cases were required to be off all systemic therapies for at least 2 wk, and off topical antipsoriatic medications for at least 1 wk. Control donors were identified from respondents to advertisements in the area (Ann Arbor, MI), had no personal or family history of psoriasis, and were free of inflammatory skin disease at the time of biopsy. The study was approved by the Institutional Review Board of the University of Michigan Medical School.
Immune cell isolation
Single cell suspensions were prepared from PBMC and skin tissue samples. Skin biopsy samples were incubated in 50 U/ml dispase (BD Biosciences) at 37°C for 90 min. Epidermis and dermis were teased apart with fine forceps. The dermal portions were then cut into 1-mm pieces and digested in collagenase for 2 h at room temperature. Single cell suspensions of epidermal portions were generated by incubation in Cell Dissociation buffer (Invitrogen) at 37°C for 2 h. Skin explant cultures of T cells from skin biopsies were prepared as described (31).
Immune cells including T cells and CD14+ or CD11c+ myeloid APCs were enriched using paramagnetic beads (StemCell Technologies) and sorted from stained single cell suspensions using a high-speed cell sorter (FACSAria; BD Immunocytometry Systems) as we described (32, 33). Cell purity was >98% as confirmed by flow cytometry (LSR II; BD Immunocytometry Systems). CD14+ or CD11c+ myeloid APCs were used to stimulate T cells as indicated.
APC activation and cytokine production
Fresh peripheral blood CD11c+ APCs (0.5 × 106/ml) were incubated for 72 h with or without recombinant human IFN-γ (200 ng/ml; R&D Systems). These cells were washed and used for T cell stimulation or activated for 12 h with LPS (1 μg/ml; Sigma-Aldrich) or incubated 3 days (1 × 106 cells/ml) in the presence of LPS to detect cytokine levels in supernatants. All Abs were from R&D Systems, except IL-23p19 from eBioscience.
T cell culture system
Myeloid APCs were cocultured with peripheral blood T cells in ratios from 1:3 to 1:10 (0.5 × 106 T cells/ml) for 4 days in the presence of anti-CD3 (2.5–5 μg/ml) and anti-CD28 (1.2–2.5 μg/ml) mAbs (BD Biosciences). Different cytokines and neutralizing Abs or their combinations including IL-1α (2.5 ng/ml), IL-1β (2.5 ng/ml), IL-23 (10 ng/ml), anti-IL-4 (1 μg/ml), anti-IFN-γ (2 μg/ml), anti-IL-1 (1 μg/ml anti-IL-1R plus 1 μg/ml anti-IL-1α) were used as indicated (all from R&D Systems). Cells were subjected to flow cytometric phenotyping, intracellular cytokine staining, and transcript detection by real-time PCR. Culture supernatants were collected for detection of IL-17 by ELISA (R&D Systems). For flow cytometry analysis, cells were first stained extracellularly with specific Abs, then fixed and permeabilized with Perm/Fix solution (eBioscience), and finally stained intracellularly with specific Abs against the indicated cytokines (BD Biosciences). Samples were acquired on a LSR II (BD Biosciences) and data were analyzed with DIVA software (BD Biosciences).
Small interfering RNA (siRNA)4 knockdown of human IL-23 gene expression
HEK293 cells were transfected with a Flag-tagged IL-23 expression plasmid and either a nonfunctional scrambled control siRNA or IL-23-specific siRNA using Lipofectamine 2000 (Invitrogen). After the siRNA treatment, the human IL-23 silencing efficiency was measured by Western blot analysis using anti-Flag tag (data not shown). Peripheral blood myeloid APCs were transfected with the siRNA or pmaxGFP vector using Nucleofector technology (Macrophages Nucleofector kit; Amaxa) as we described (34). The transfection efficiency reached 60–80% as confirmed by pmaxGFP vector transfection.
Analysis of human β-defensin (HBD)-2 induction in keratinocytes
Normal human keratinocytes were grown in serum-free medium optimized for high-density keratinocyte growth (medium 154; Cascade Biologics) and used for experiments in the second or third passage at subconfluence. All cells were plated at 5000 cells/cm2, and switched to basal Medium 154 lacking growth factors at 24 h before assay. In some experiments, the calcium concentration was increased from 0.1 to 1.4 mM to enhance production of HBD-2 (35, 36). HBD-2 in supernatants was measured by ELISA using Abs and recombinant protein from PeproTech as described (37).
Migration assays were performed in a Transwell system with a polycarbonate membrane of 6.5 mm diameter with a 3-μm pore size as we described (32). Purified T cell subsets were added to the upper chamber, and CCL20 (5 ng/ml; R&D Systems) was added to the lower chamber. After 4 h of incubation at 37°C, the phenotype and number of T cells in the upper and lower chambers was determined by FACS.
Quantification of gene expression
Quantitative real-time PCR was performed on control, lesional, and nonlesional skin samples from 10 psoriatic patients and 10 normal controls. Primers for the genes IL-1α (catalog no. PPH00690A), IL-1β (catalog no. PPH00171A), DEFB4 (catalog no. PPH11010A), IL-12A (p35, catalog no. PPH00544B), and IL-12B (p40, catalog no. PPH00545A) were obtained from Superarray Biosciences. Results were normalized to the expression of the housekeeping gene, ribosomal protein, large PO (RPLPO, 36B4, catalog no. PPH21138E). Quantification of gene expression in the cultured myeloid APCs was performed as we described (10, 11). The gene transcripts were quantified in a MasterCycler RealPlex system (Eppendorf Scientific) and expressed as mRNA quantities normalized to GAPDH levels.
Skin biopsy samples were stained with anti-CD4 or anti-CD8 Ab as described (32). The staining was detected using the one-step avidin-biotin complex technique (Vectastain Elite ABC kit; Vector Laboratories).
The Wilcoxon rank-sum test was used to determine pairwise differences and the χ2 test used to determine differences between groups. A value for p < 0.05 was considered as significant. Differences in phenotype of T cell subsets were tested with the paired Student’s t test. Correlation was tested by Spearman’s test. All statistical analysis was done on Statistica software (StatSoft).
IL-17+ T cells are increased in psoriatic plaques
Th17 cells are thought to play a role in psoriatic pathogenesis (16, 30). However, the phenotype and distribution of IL-17+ T cells in patients with psoriasis remain poorly defined. We investigated the number and distribution of CD4+ and CD8+ IL-17+ T cells in peripheral blood (Fig. 1,A) and skin (Fig. 1, A–C) of healthy donors and patients with psoriasis. The highest percentage (Fig. 1, A and B) and absolute number (Fig. 1,C) of CD4+ and CD8+ IL-17+ T cells were observed in psoriatic skin lesions (plaques). Notably, we observed an increased number of CD8+ IL-17+ T cells in psoriatic skin for the first time (Fig. 1,C). We further analyzed the expression of IFN-γ and IL-17 per single cell level. Interestingly, 30–50% IL-17+ T cells coexpressed IFN-γ in the skin from psoriatic plaque (Fig. 1,D). After enzymatic separation of epidermis and dermis, we found an increased number of both CD4+ and CD8+ IL-17+ T cells in lesional psoriatic dermis, relative to uninvolved skin from persons with psoriasis or healthy donors. However, in plaque epidermis most of the IL-17+ T cells were CD8+ (Fig. 1,E), whereas CD8+ IL-17+ T cells were virtually absent from healthy donor epidermis (Fig. 1 E). The data demonstrate the prevalence, phenotype, and distribution of IL-17+ T cells in patients with psoriasis, and indicate that psoriatic skin is an environment containing abundant IL-17+ T cells including Th17 cells and CD8+ IL-17+ T cells.
IFN-γ+ T cells in patients with psoriasis
As a control for relative IL-17+ T cell quantification, we examined the distribution of CD4+, CD8+, and IFN-γ+ T cells in psoriatic skin in patients with psoriasis. Consistent with previous reports (23, 26, 38), we observed a large number of CD4+ and CD8+ T cells in psoriatic dermis and an increased number of primarily CD8+ T cells in psoriatic epidermis (Fig. 2,A). The epidermal-dermal distribution of CD4+ and CD8+ IFN-γ+ T cells is similar for T cells expressing IFN-γ and IL-17 in psoriatic skin (Fig. 1). It has been hypothesized that Th1 cells promote psoriatic pathogenesis (23, 26, 38). Consistent with these observations, high levels of IFN-γ+ T cells (Fig. 2,B) and IFN-γ transcripts (Fig. 2 C) were also detected in psoriatic plaques. In our experiments, we therefore analyzed the relationship between IFN-γ and IL-17+ T cells in psoriatic pathogenesis.
Psoriatic myeloid APCs induce IL-17+ T cells
APCs contribute to T cell polarization. It is thought that myeloid-derived gene products contribute to pathogenic inflammation in psoriasis (39). We therefore investigated a potential role for myeloid APCs in inducing IL-17+ T cells. Myeloid APCs were found in psoriatic skin (Fig. 3, A and B). Although numerically CD14+ cells are the major APCs in the skin, CD11c+ cells may be functionally the most powerful APCs in the skin. Therefore, we initially sorted both CD14+ and CD11c+ myeloid APCs from peripheral blood and skin plaques of people with psoriasis and healthy donors. We observed that CD14+ and CD11c+ myeloid APCs induced similar levels of Th17 cells (Fig. 3,C and data not shown). Interestingly, APCs from psoriatic peripheral blood and skin lesions were significantly more efficient than those from healthy donors in inducing IL-17 production (Fig. 3,C) and IL-17+ T cells (Fig. 3,D). Myeloid APCs isolated from psoriatic plaques were superior to those isolated from blood in IL-17+ T cell induction (Fig. 3, C and D), although these APCs induced comparable levels of IFN-γ production. Myeloid APCs induced both CD4+ and CD8+ IL-17+ T cells (Fig. 3,D). We performed similar experiments with responder T cells from normal donors and psoriatic patients. We observed that APCs from psoriatic skin lesions induced comparable Th17 cell development in responder T cells from normal donors and psoriatic patients (Fig. 3, C and D, and data not shown). Altogether, these data indicate that psoriatic myeloid APCs potently induce IL-17+ T cells, and may thereby stimulate and maintain the IL-17+ T cell pool in patients with psoriasis.
IFN-γ programs myeloid APCs to stimulate IL-17+ T cells
We next studied why psoriatic myeloid APCs are potent inducers of IL-17+ T cells. The contribution of IFN-γ was investigated, as IFN-γ is increased in serum of persons with psoriasis (40). IFN-γ+ T cells are enriched in psoriatic skin (Fig. 2), and previous studies implicated IFN-γ and Th1 cells in psoriasis pathogenesis (23, 25, 26). To test the hypothesis that IFN-γ may program myeloid APCs to stimulate IL-17+ T cells, CD11+ cells from the blood of donors who did not have psoriasis were conditioned with IFN-γ and tested for their capacity to induce IL-17+ T cells. IFN-γ profoundly increased the capacity of these CD11c+ cells to elicit IL-17+ T cells (Fig. 4, A and B). We also conditioned peripheral blood myeloid APCs from psoriatic patients with exogenous IFN-γ, and observed that IFN-γ was able to further enhance the ability of normal and psoriatic myeloid APCs to induce IL-17-secreting T cells (Fig. 4, C and D). The data suggest that IFN-γ released by psoriatic T cells (Fig. 2) may condition myeloid APCs to induce IL-17+ T cells.
IL-1 and IL-23 mediate IFN-γ-stimulated induction of IL-17+ T cells by myeloid APCs
We further investigated the mechanism by which IFN-γ programs myeloid APCs to induce IL-17+ T cells. We showed that exogenous IL-1 and IL-23 were each capable of enhancing the induction of IL-17+ T cells by blood CD11c+ cells (Fig. 5,A). We next analyzed the expression of IL-1 and IL-23 in CD11c+ cells treated with IFN-γ. IFN-γ moderately increased the expression of IL-12p35. However, IFN-γ dramatically increased the expression of IL-1, IL-12p40, and IL-23p19 (Fig. 5 B). Similar effects of IFN-γ were observed on CD11c+ and CD14+ APCs. The data indicate that the effects of IFN-γ are more pronounced on IL-23 than IL-12p70.
We next examined the role of CD11c+-derived IL-1 and IL-23 in inducing memory IL-17+ T cells. Reliable and specific neutralizing Abs against IL-23p19 are not commercially available, and anti-IL-12p40 neutralizing Ab blocks both IL-12 and IL-23. Therefore, to conclusively block IL-1 and IL-23, we used neutralizing Abs against IL-1α and IL-1R and designed three siRNA sequences, which specifically block human IL-23 (data not shown). Blockade of IL-1 and IL-23 separately each reduced CD11c+-mediated induction of IL-17+ T cells, and simultaneous blockade of both cytokines abrogated the IL-17 response (Fig. 5,C). We extended these observations to patients with psoriasis. Consistent with the high levels of IL-17+ T cells (Fig. 1) and of IL-17+-inducing myeloid APCs (Fig. 3), we detected high levels of IL-1β and IL-23 transcripts in psoriatic plaques (Fig. 5, D and E). Taken together, our data suggest that IFN-γ programs myeloid APCs to induce IL-17+ T cells through IL-1 and IL-23 in patients with psoriasis.
CCR6+ IL-17+ T cells and CCL20 in the psoriatic environment
We next examined how IL-17+ T cells traffic to the psoriatic environment. We found that CD4+ and CD8+ IL-17+ T cells derived from psoriatic plaque highly expressed CCR6 (Fig. 6, A and B). We therefore asked whether IL-17+ T cells could migrate toward CCL20, the ligand for CCR6. We observed that T cells efficiently migrated in response to CCL20, and that the migrating cells were enriched for IL-17+ T cells (from 0.2% IL-17− cells in the upper chamber to 11% IL-17+ T cells in the lower chamber) (Fig. 6,C). We further tested the role of IFN-γ in CCL20 production. We observed that IFN-γ stimulated CCL20 production from CD11c+ APCs (Fig. 6,D). High levels of CCL20 mRNA were detected in lesional psoriatic skin (39, 41) (Fig. 6 E). The data suggest that IFN-γ derived from psoriatic T cells induces CCL20 and promotes homing of IL-17+ T cells to the psoriatic environment.
Psoriatic IL-17+ T cells are functional
We next asked whether myeloid APC-induced IL-17+ T cells are functional. HBD-2 is an important component of skin innate immunity (35, 44). Increased HBD-2 copy number has recently been shown to be a risk factor for development of psoriasis (45). We confirmed that high levels of HBD-2 transcripts are present in psoriatic plaques (Fig. 7,A). Furthermore, IL-17 induced a dose-dependent increase in secreted HBD-2 protein in keratinocytes, which could be blocked by a neutralizing Ab specific for the human IL-17R (anti-IL-17R) (Fig. 7,B). We next generated IL-17+ T cells with psoriatic myeloid APCs, collected the conditioned medium from these cultures, assayed them for IL-17 protein, and treated normal human keratinocytes with a 1/5 dilution of conditioned medium. The T cell supernatants strongly induced human HBD-2 secretion by keratinocytes (Fig. 7,C). Moreover, anti-IL-17R blocked the induced HBD-2 expression (Fig. 7,C). Furthermore, the concentrations of IL-17 in the T cell supernatants were positively correlated with the levels of HBD-2 secreted by keratinocytes (Fig. 7,D). We next examined whether IFN-γ has an effect on HBD-2 production. IFN-γ alone had no detectable effect on HBD-2 secretion by keratinocytes. However, IFN-γ synergistically increased HBD-2 production induced by IL-17 (Fig. 7,E). The data indicate that IL-17+ T cells generated by psoriatic myeloid APCs are functional, and that IFN-γ and IL-17 synergistically promote the innate immune function of keratinocytes. Based on all our findings, we propose a novel mode of interaction among Th1, IL-17+ T cells, and APCs in human autoimmune disease (Fig. 7 F): IFN-γ derived from Th1 and other cells promotes tissue homing of IL-17+ T cell by stimulating local CCL20 production and stimulates IL-17+ T cells by programming IL-17-inducing myeloid APCs.
Th17 cells are thought to play a role in psoriatic pathogenesis (16, 30). In this report we have investigated the phenotype, distribution, trafficking, development, and function of IL-17+ T cells in healthy humans and patients with psoriasis. We show that both CD4+ and CD8+ T cells express IL-17 in normal donors as well as in people with psoriasis. Although the phenotype of human Th17 cells has not yet been fully defined, CD4+ IL-17+ T cells (Th17) are postulated to play a role in psoriasis pathogenesis (16, 30). Entry of CD8+ T cells into the epidermis is necessary for the epidermal hyperproliferative response in psoriasis (43, 46). We observed high levels of CD8+ IL-17+ T cells in the epidermis of psoriatic lesions. CD8+ IL-17+ T cells are thus ideally positioned to respond to potential keratinocyte autoantigens on HLA class I molecules, which have been genetically implicated in psoriasis (47). Our observations support the hypothesis that CD8+ IL-17+ T cells are critical mediators of the persistently altered epidermal growth and differentiation and the local inflammation that is characteristic of psoriasis. We have also observed CD8+ IL-17+ T cells in cancers (10, 11) and colitis (W. Zou et al., unpublished observation). Our data provide the first evidence that CD8+ IL-17+ T cells are at least as important as Th17 cells (16, 30) in autoimmune diseases, including but not limited to psoriasis.
We further characterize the phenotype of human psoriatic IL-17+ T cells: CD103+CCR6+ IL-17+ T cells are effector T cells often found in environments with chronic inflammation (1, 3). It is therefore not surprising that human IL-17+ T cells highly express CD103, which may facilitate trafficking of IL-17+ cells into inflammatory tissues (42, 43). We confirm that psoriatic skin is an environment enriched with CCL20, and show that CCL20 is triggered by IFN-γ in myeloid APCs. Furthermore, we show that psoriatic Th1 cells are one of the major sources of IFN-γ, and that IL-17+ T cells efficiently migrate toward a CCL20-enriched psoriatic environment via CCR6. Our data lead us to propose a first mode of potential interaction between Th1 and IL-17+ T cells in psoriasis: IFN-γ derived from Th1 cells (and other cells) promotes trafficking of IL-17+ T cells to the psoriatic environment through the induction and maintenance of local CCL20 production.
There are <1% CD4+ and <0.5% CD8+ IL-17+ T cells in peripheral blood of healthy humans (10, 11). In contrast, high levels of Th17 and CD8+ IL-17+ T cells are observed in psoriatic plaques. How does this dramatic induction occur? In addition to migration from peripheral blood, IL-17+ T cells may be induced within the psoriatic environment. It has been reported that myeloid cell-derived genes contribute to pathogenic inflammation in psoriasis (39). We demonstrate that myeloid APCs including macrophages and myeloid dendritic cells potently induce human IL-17+ T cells. Our observation may explain why IL-17+ T cells are often found in inflammatory tissues and organs. In support of this concept, we show that myeloid APCs isolated from psoriatic plaques potently stimulate IL-17+ T cells. Additionally, our observation that circulating myeloid APCs from people with psoriasis promote IL-17+ T cell development may partially explain why persons with psoriasis experience inflammation at distinct anatomical sites, including skin plaques, arthritis, and atherosclerosis. Increased circulating IFN-γ (48) may activate circulating APCs, allowing them to enter tissue and promote expansion of IL-17+ T cells. Interestingly, recent studies in mouse models of chronic psoriasiform skin inflammation support pathogenic involvement of activated macrophages, although IL-17+ T cells have not been specifically investigated in these models (49, 50).
How and why do activated myeloid APCs contribute to psoriatic skin inflammation? Th1 cells can suppress Th17 cell differentiation through IFN-γ (1, 2, 3, 5, 51). However, this presents the paradox of why Th17 and Th1 cells often coexist in autoimmune diseases (17, 18, 20) including psoriasis (24). We demonstrate that psoriatic T cells produce IFN-γ, IFN-γ triggers myeloid APCs to produce IL-1 and IL-23, and in turn induce IL-17+ T cells. Our data therefore demonstrate a second mode of potential interaction between Th1 and IL-17+ T cells in psoriasis: IFN-γ derived from Th1 cells (and other cells) activates psoriatic myeloid APCs, and the latter promote IL-17+ T cell development through IL-1 and IL-23 in the psoriatic environment. Therefore, IFN-γ may possibly play dual roles in regulating the IL-17+ T cell pool: IFN-γ targets APCs to initiate and promote Th17 polarization (this study) whereas it targets naive T cells (1, 2, 3, 5, 51) to suppress Th17 polarization.
In addition to promoting the trafficking and development of IL-17+ T cells, IFN-γ also regulates the function of IL-17+ T cells. HBDs are greatly enriched in the psoriatic environment (35) and play a role in increasing genetic susceptibility to psoriasis (45). Interestingly, we demonstrate that HBD-2 is induced by IL-17 and its expression is synergistically enhanced by IFN-γ, similar to synergistic effects of IFN-γ and IL-17 on induction of IL-6, IL-8, GRO-α, and GM-CSF (52, 53). Our data thereby illustrate a third mode of potential interaction between Th1 and IL-17+ T cells in psoriasis: IFN-γ derived from Th1 (and other cells), and IL-17 derived from IL-17+ T cells, may synergistically promote keratinocyte function. The three modes of interaction described in this study suggests a novel, collaborative contribution of IL-17+ T cells and IFN-γ+ cells including Th1 cells to inflammatory reactions and autoimmune diseases, including psoriasis.
In summary, we show that IFN-γ may promote trafficking, induction, and function of IL-17+ T cells in people with psoriasis. This study suggests a novel mechanistic interaction between Th1 and Th17 cells, challenges the view that Th1 cells suppress Th17 cell development, and suggests a collaborative contribution of Th1 and Th17 to human autoimmune diseases. Improved mechanistic insight into the collaborative interactions between these central regulatory players promises novel approaches to management of autoimmune diseases.
We thank the volunteers who provided blood and skin samples for this study, and acknowledge the skilled technical assistance of Lynda Hodges, Kathleen McCarthy, Suzan Rehbine, and Thy Thy Do.
The authors have no financial conflict of interest.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
This work was supported by the Dermatology Foundation (to A.B. and J.E.G.), the National Psoriasis Foundation (to A.B.), the American Skin Association (to J.E.G.), Grant AR052889 from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases (to J.T.E.), and Grant CA99985 from the National Cancer Institute (to W.Z.).
Abbreviations used in this paper: siRNA, small interfering RNA; HBD, human β-defensin.