Both Th1 and Th17 Are Immunopathogenic but Differ in Other Key Biological Activities

Cox, Catherine A.; Shi, Guangpu; Yin, Hongen; Vistica, Barbara P.; Wawrousek, Eric F.; Chan, Chi‐Chao; Gery, Igal

doi:10.4049/jimmunol.180.11.7414

Cited by 60 publications

(88 citation statements)

References 52 publications

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“…Since then, Th17 cells have been implicated in the pathogenesis of several autoimmune diseases, including multiple sclerosis and rheumatoid arthritis. In the case of autoimmune diabetes, the function of Th17 cells has been a topic of much debate (28)(29)(30). Some researchers have argued for a critical role of Th17 cells especially in later effector processes (28), although others have cautioned about possible misinterpretations of findings from Th17 transfer experiments because of the conversion to or expansion of Th1 cells (29,31).…”

Section: Discussionmentioning

confidence: 99%

Expression of CXCR3 on Specific T Cells Is Essential for Homing to the Prostate Gland in an Experimental Model of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

Breser

Motrich

Sánchez

et al. 2013

The Journal of Immunology

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Experimental autoimmune prostatitis (EAP) is considered a valid model for the human disease chronic prostatitis/chronic pelvic pain syndrome. In this report, we analyzed phenotypic characteristics of T cells that gain access to the prostate and induce leukocyte recruitment in mice with different susceptibility to EAP. After EAP induction, NOD mice developed a specific cellular response characterized by a mixed Th1/Th17 pattern with specific T cells mainly expressing CXCR3 that infiltrated and damaged the prostate. In contrast, BALB/c mice, as well as NOD-IFN-γ−/−, exhibited only Th17 cells mainly expressing CCR6 that were not capable of infiltrating the prostate gland. Adoptive transfer experiments of T cells from NOD or NOD–IFN-γ−/− mice to NOD-SCID recipients showed that only T cells from NOD mice successfully infiltrated the prostate. However, after “in vitro” or “in vivo” treatment with rIFN-γ, T cells from NOD–IFN-γ−/− mice became capable of homing to the prostate and induced leukocyte recruitment. Chemokine levels in prostate tissue from NOD mice showed increased expression levels of CXCR3 ligands. Additional experiments using adoptive transfer of sorted CXCR3+CD3+ T cells or administrating a CXCR3 antagonist treatment confirmed these previous results. Altogether, our results demonstrate that the expression of CXCR3 on effector T cells is essential for their homing to the prostate gland in EAP. CXCR3 emerges as a potential therapeutic target to control chronic prostatitis/chronic pelvic pain syndrome.

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Section: Discussionmentioning

confidence: 99%

Expression of CXCR3 on Specific T Cells Is Essential for Homing to the Prostate Gland in an Experimental Model of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

Breser

Motrich

Sánchez

et al. 2013

The Journal of Immunology

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“…Nevertheless, a role for IFN-g in autoimmunity cannot be neglected and blockade of IFN-g in patients with CD is currently being tested for efficacy in phase 2 clinical trials (19). Furthermore, the importance of IFN-g during inflammation has been highlighted in animal models: intestinal inflammation induced by Helicobacter hepaticus depended on both IFN-g and IL-17 functions (20); both myelin-specific IL-12-and IL-23-polarized T cells are able to induce experimental autoimmune encephalomyelitis (EAE) (21,22); either Th1 or Th17 cells can be pathogenic during ocular inflammation (23,24); and severe arthritis in the proteoglycan-induced arthritis model depends on IFN-g and not IL-17 (25,26).…”

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confidence: 99%

Human Th17 Cells Comprise Heterogeneous Subsets Including IFN-γ–Producing Cells with Distinct Properties from the Th1 Lineage

Boniface¹,

Blumenschein²,

Brovont-Porth³

et al. 2010

The Journal of Immunology

171

132

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Th17 cells have been named after their signature cytokine IL-17 and accumulating evidence indicates their involvement in the induction and progression of inflammatory diseases. In addition to IL-17 single-producing T cells, IL-17/IFN-γ double-positive T cells are found in significantly elevated numbers in inflamed tissues or blood from patients with chronic inflammatory disorders. Because IFN-γ is the classical Th1-associated cytokine, the origin and roles of these subsets remain elusive. In this paper, we show that not only IL-17+/IFN-γ+ but also IFN-γ+ (IL-17−) cells arise under Th17-inducing condition and have distinct properties from the Th1 lineage. In fact, these populations displayed characteristics reminiscent to IL-17 single-producing cells, including production of IL-22, CCL20, and induction of antimicrobial gene expression from epithelial cells. Live sorted IL-17+ and Th17–IFN-γ+ cells retained expression of IL-17 or IFN-γ after culture, respectively, whereas the IL-17+/IFN-γ+ population was less stable and could also become IL-17 or IFN-γ single-producing cells. Interestingly, these Th17 subsets became “Th1-like” cells in the presence of IL-12. These results provide novel insights into the relationship and functionality of the Th17 and Th1 subsets and have direct implications for the analysis and relevance of IL-17 and/or IFN-γ–producing T cells present in patients’ peripheral blood and inflamed tissues.

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“…We confirmed this expression on in vivoinduced Th17 cells but could detect neither significant CCR6 nor CCR4 expression on the surface of 1 wk old in vitro-generated Th17 cells. In contrast, other groups reported CCR6 surface expression on in vitro-generated Th17 cells [45,47,48]. However, Hirota et al demonstrated that stimulation with IL-1b is mandatory for optimal CCR6 expression of in vitro-primed Th17 cells [48].…”

Section: Discussionmentioning

confidence: 56%

“…This suggests that in vitro-generated Th17 cells differ from their in vivo-primed counterparts in their migratory potential as well as in the stability of the Th17 phenotype, which has recently been demonstrated [41,42]. Only a few reports showed direct inflammatory ability of in vitro-primed Th17 in vivo, yet [43,45]. Langrish et al as well as others showed that Th17 cells may induce passive EAE.…”

Section: Discussionmentioning

confidence: 94%

“…Thus, the stronger proliferation of Th17 cells in vivo together with the production of IFN-g might be responsible for the more severe gastritis symptoms induced by Th17 cells in this study [43]. Cox et al showed that in vitro-induced Th1 as well as Th17 cells induce eye inflammation in vivo [45]. Although Th17 cells were less efficient than Th1 cells, this indicates again that homing into the eyes requires different migratory receptors than homing into the inflamed knee joint or the footpad.…”

Section: Discussionmentioning

confidence: 99%

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In vitro‐induced Th17 cells fail to induce inflammation in vivo and show an impaired migration into inflamed sites

et al. 2010

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Recently, IL-17 produced by Th17 cells was described as pro-inflammatory cytokine with an eminent role in autoimmune diseases, e.g. rheumatoid arthritis. A lack of IL-17 leads to amelioration of collagen-induced arthritis. IL-17 induction in naïve CD41 T cells depends on IL-6 and TGF-b and is enhanced by IL-23. The in vivo inflammatory potential of in vitroprimed Th17 cells however, remains unclear. Here, we show that, although IL-17 neutralisation results in amelioration of murine OVA-induced arthritis, in vitro-primed Th17 cells cannot exacerbate arthritic symptoms after adoptive transfer. Furthermore, Th17 cells cannot induce an inflammatory delayed type hypersensitivity reaction because they fail to migrate into inflamed sites, possibly due to the lack of CXCR3 expression. Also, re-isolated Th17 cells acquired IFN-c expression, indicating instability of the Th17 phenotype. Taken together, the data show that IL-6, TGF-b and IL-23 might not provide sufficient signals to induce ''fully qualified'' Th17 cells.Key words: Cell migration . Inflammation . Th17 cells IntroductionIn the last years, the pro-inflammatory cytokines IL-23 and IL-17 came into focus to play a major role in inflammatory autoimmune diseases. IL-23, a heterodimeric protein consisting of p40 (shared subunit with IL-12) and p19, was identified as an important factor to induce or maintain inflammatory diseases, for p19-deficient mice are resistant to EAE and colitis [1,2]. IL-17 acts on multiple cell types to evoke the release of other pro-inflammatory cytokines like TNF-a, IL-1b or IL-6 as well as chemokines like IL-8 to attract neutrophils or macrophages to the inflamed site [3,4]. This may lead to a rising inflammatory response. In addition, IL-17 directly causes bone and cartilage destruction via upregulation of RANK-L and therefore, an eminent role of IL-17 in autoimmune diseases, like rheumatoid arthritis, was reported [5,6]. In 2006 Veldhoen et al. and others showed that the combination of IL-6 and TGF-b is sufficient to induce IL-17 expression by CD4 T cells in vitro [7]. Furthermore, by blocking Th1 and Th2 differentiation pathways, the efficiency of Th17 differentiation can be enhanced. Therefore, IL-17-producing Th cells were claimed to represent a distinct Th-cell lineage, termed Th17 cells [7][8][9]. However, IL-1b was reported to be necessary for Th17 induction in vivo and IL-6-independent pathways for IL-17 induction may exist, for IL-6-deficient mice show diminished but detectable levels of Th17 cells [10,11]. RORgT was claimed to be the Th17 lineage-specific transcription factor and sufficient to Ã These authors contributed equally to this work. To directly address the question on the role of joint-specific Th17 cells for arthritis pathogenesis we employed the OVAinduced arthritis (OIA) model. This arthritis model allows the direct analysis of OVA-specific T cells upon adoptive transfer in vivo. Using OIA and delayed type hypersensitivity (DTH) reaction, we show that in vitro-primed Th17 cells lack proinflammatory potential in vi...

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Both Th1 and Th17 Are Immunopathogenic but Differ in Other Key Biological Activities

Cited by 60 publications

References 52 publications

Expression of CXCR3 on Specific T Cells Is Essential for Homing to the Prostate Gland in an Experimental Model of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

Expression of CXCR3 on Specific T Cells Is Essential for Homing to the Prostate Gland in an Experimental Model of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

Human Th17 Cells Comprise Heterogeneous Subsets Including IFN-γ–Producing Cells with Distinct Properties from the Th1 Lineage

In vitro‐induced Th17 cells fail to induce inflammation in vivo and show an impaired migration into inflamed sites

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