Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model

Hirota, Keiji; Yokota, Hiroyuki; Hashimoto, Motomu; Maeda, Shinji; Teradaira, Shin; Sugimoto, Naoshi; Yamaguchi, Tomoyuki; Nomura, Takashi; Ito, Hiromu; Nakamura, Takashi; Sakaguchi, Noriko; Sakaguchi, Shimon

doi:10.1084/jem.20071397

Cited by 820 publications

(817 citation statements)

References 29 publications

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“…Only 5-6% of all thymic gd T cells were CCR6 1 , but those constituted approximately 75% of all thymic IL-17A-producing gd T cells. This finding is in compliance with the notion that Th17 gd T cells are for the most part CCR6 1 [25][26][27]. Conversely, CCR6 1 thymic gd T cells did not produce IFN-g (Fig.…”

supporting

confidence: 90%

CCR6 and NK1.1 distinguish between IL‐17A and IFN‐γ‐producing γδ effector T cells

et al. 2009

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cd T cells are a potent source of innate IL-17A and IFN-c, and they acquire the capacity to produce these cytokines within the thymus. However, the precise stages and required signals that guide this differentiation are unclear. Here we show that the CD24 low CD44 high effector cd T cells of the adult thymus are segregated into two lineages by the mutually exclusive expression of CCR6 and NK1.1. Only CCR6 1 cd T cells produced IL-17A, while NK1.1 1 cd T cells were efficient producers of IFN-c but not of IL-17A. Their effector phenotype correlated with loss of CCR9 expression, particularly among the NK1.1 1 cd T cells. Accordingly, both cd T-cell subsets were rare in gut-associated lymphoid tissues, but abundant in peripheral lymphoid tissues. There, they provided IL-17A and IFN-c in response to TCR-specific and TCR-independent stimuli. IL-12 and IL-18 induced IFN-c and IL-23 induced IL-17A production by NK1.1 1 or CCR6 1 cd T cells, respectively. Importantly, we show that CCR6 1 cd T cells are more responsive to TCR stimulation than their NK1.1 1 counterparts. In conclusion, our findings support the hypothesis that CCR6 1 IL-17A-producing cd T cells derive from less TCR-dependent selection events than IFN-c-producing NK1.1 1 cd T cells.Key words: gd T cells . CCR6 . IFN-g . IL-17A . Innate lymphocytes . NK1.1 Introduction IL-17A and IFN-g are generally regarded as pro-inflammatory effector cytokines that can be produced by Th cells but also by innate lymphocytes such as NK cells, NKT cells and gd T cells. While macrophage activation is supposed to be the main role of IFN-g, the induction of granulopoiesis is ascribed as a key biological function of IL-17A [1]. It is currently emerging that gd T cells are a potent source of IL-17A in the early phases of immune responses (reviewed in [2]). gd T cells constitute a large fraction of all IL-17A-producing cells in healthy mice and humans and are able to secrete IL-17A much more rapidly than CD4 1 Th17 cells [3][4][5]. These observations led to the concept that gd T cells are important players in a transitional response between innate and adaptive immune reactions [6]. The production of innate IL-17A by gd T cells appears to be essential in situations where an effective defence against extra-cellular bacteria or fungi relies on the fast mobilization of neutrophils [4,[6][7][8][9]. Moreover, IL-17A-producing gd T cells have been described to play important roles in immunopathologic diseases such as collageninduced arthritis [10], experimental pulmonary fibrosis [11], and in experimental autoimmune encephalitis [12,13].In contrast to CD4 1 Th cells that can develop into Th17 cells after encounter of specific cognate TCR Ag [14][15][16], it is not clear which stimuli induce IL-17A production by gd T cells in vivo. This essentially results from a lack of information about physiological gd TCR ligands. However, the current literature suggests that the decision whether a gd T cell will produce IL-17A is linked to 3488thymic development. Jensen et al. introduced a concept th...

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confidence: 90%

CCR6 and NK1.1 distinguish between IL‐17A and IFN‐γ‐producing γδ effector T cells

et al. 2009

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“…Finally, Th17 has been found involved in arthritis development in CIA, but its role in vascular dysfunction in this context has not been described 43, 44. Moreover, its role in vascular dysfunction such as atherosclerosis is controversial 45, 46, 47.…”

Section: Discussionmentioning

confidence: 99%

Aortic VCAM‐1: an early marker of vascular inflammation in collagen‐induced arthritis

Denys

Clavel

Lemeiter

et al. 2016

J Cellular Molecular Medi

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Cardiovascular disease (CVD) is a major cause of morbidity and mortality in rheumatoid arthritis (RA). There are limited experimental data on vascular involvement in arthritis models. To study the link between CVD and inflammation in RA, we developed a model of vascular dysfunction and articular inflammation by collagen‐induced arthritis (CIA) in C57Bl/6 (B6) mice. We studied the expression of vascular inflammatory markers in CIA with and without concomitant hyperlipidic diet (HD). Collagen‐induced arthritis was induced with intradermal injection of chicken type‐II collagen followed by a boost 21 days later. Mice with and without CIA were fed a standard diet or an HD for 12 weeks starting from the day of the boost. Arthritis severity was evaluated with a validated clinical score. Aortic mRNA levels of vascular cell adhesion molecule‐1 (VCAM‐1), inducible nitric oxide synthase (iNOS) and interleukin‐17 were analysed by quantitative RT‐PCR. Vascular cell adhesion molecule‐1 localization in the aortic sinus was determined by immunohistochemistry. Atherosclerotic plaque presence was assessed in aortas. Collagen‐induced arthritis was associated with increased expression of VCAM‐1, independent of diet. VCAM‐1 overexpression was detectable as early as 4 weeks after collagen immunization and persisted after 15 weeks. The HD induced atheroma plaque formation and aortic iNOS expression regardless of CIA. Concomitant CIA and HD had no additive effect on atheroma or VCAM‐1 or iNOS expression. CIA and an HD diet induced a distinct and independent expression of large‐vessel inflammation markers in B6 mice. This model may be relevant for the study of CVD in RA.

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“…Moreover, CD103 can act as a co-activation molecule in human T lymphocytes [38] and could play a similar role in the activation of iNKT17 cells in the pancreas. While CCR6 is involved in the recruitment of Th17 cells in the target tissue in autoimmune CIA [39], the recruitment of iNKT17 cells in the pancreas is probably independent of CCR6 since most of them do not express this molecule. Alternatively, lack of expression of CCR6 might be due to downregulation upon entry into inflamed pancreas.…”

Section: Discussionmentioning

confidence: 99%

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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Invariant natural killer T (iNKT) cells are a distinct lineage of innate-like T lymphocytes and converging studies in mouse models have demonstrated the protective role of iNKT cells in the development of type 1 diabetes. Recently, a new subset of iNKT cells, producing high levels of the pro-inflammatory cytokine IL-17, has been identified (iNKT17 cells). Since this cytokine has been implicated in several autoimmune diseases, we have analyzed iNKT17 cell frequency, absolute number and phenotypes in the pancreas and lymphoid organs in non-obese diabetic (NOD) mice. The role of iNKT17 cells in the development of diabetes was investigated using transfer experiments. NOD mice exhibit a higher frequency and absolute number of iNKT17 cells in the lymphoid organs as compared with C57BL/6 mice. iNKT17 cells infiltrate the pancreas of NOD mice where they express IL-17 mRNA. Contrary to the protective role of CD4 1 iNKT cells, the CD4 À iNKT cell population, which contains iNKT17 cells, enhances the incidence of diabetes. Treatment with a blocking anti-IL-17 antibody prevents the exacerbation of the disease. This study reveals that different iNKT cell subsets play distinct roles in the regulation of type 1 diabetes and iNKT17 cells, which are abundant in NOD mice, exacerbate diabetes development.

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Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model

Cited by 820 publications

References 29 publications

CCR6 and NK1.1 distinguish between IL‐17A and IFN‐γ‐producing γδ effector T cells

CCR6 and NK1.1 distinguish between IL‐17A and IFN‐γ‐producing γδ effector T cells

Aortic VCAM‐1: an early marker of vascular inflammation in collagen‐induced arthritis

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

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