Phenotypic and functional features of human Th17 cells

Annunziato, Francesco; Cosmi, Lorenzo; Santarlasci, Veronica; Maggi, Laura; Liotta, Francesco; Mazzinghi, Benedetta; Parente, Eliana; Filì, Lucia; Ferri, Simona; Frosali, Francesca; Giudici, Francesco; Romagnani, Paola; Parronchi, Paola; Tonelli, Francesco; Maggi, Enrico; Romagnani, Sergio

doi:10.1084/jem.20070663

Cited by 1,681 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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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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“…As measured by other studies [16,22,23], a remarkable proportion of Th17 cells also shares the ability to produce IFN-γ. These cells, producing both IL-17 and IFN-γ, are usually named Th17/Th1.…”

Section: Discussionsupporting

confidence: 64%

“…Interestingly, new studies show Th17 cells as more potent than Th1 cells in inducing disease [15], linking the cytokine IL-17 in coordinating tissue inflammation via the up-regulation of additional proinflammatory and neutrophil-recruiting cytokines and chemokines, suggesting a pro-inflammatory role in these conditions. Moreover, in Crohn's disease, the existence of a remarkable number of double positive IFNγ+/IL17+ T cells, named Th17/ Th1 cells, as well as the possibility to generate Th17/Th1 clones was reported [16]. These latter observations further support the concept that both Th1 and Th17 cells could contribute to the maintenance of inflammation in such disorders via the production of IFNγ and IL-17.…”

Section: Introductionmentioning

confidence: 62%

Th17 cells in systemic lupus erythematosus share functional features with Th17 cells from normal bone marrow and peripheral tissues

et al. 2011

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This study was designed to investigate the functional heterogeneity of human Th17 and how their plasticity shapes the nature of immune cell responses to inflammation and autoimmune diseases, such as systemic lupus erythematosus (SLE). We evaluated functional Th17 cell subsets based on the profile of cytokine production in peripheral blood (PB), bone marrow aspirates (BM) and lymph node biopsies (LN) from healthy individuals (n=35) and PB from SLE patients (n=34). Data were analysed by an automated method for merging and calculation of flow cytometric data, allowing us to identify eight Th17 subpopulations. Normal BM presented lower frequencies of Th17 (p=0.006 and p=0.05) and lower amount of IL-17 per cell (p=0.03 and p=0.02), compared to normal PB and LN biopsies. In the latter tissues were found increased proportions of Th17 producing TNF-α or TNF-α/IL-2 or IFN-γ/TNF-α/IL-2, while in BM, Th17 producing other cytokines than IL-17 was clearly decreased. In SLE patients, the frequency of Th17 was higher than in control, but the levels of IL-17 per cell were significantly reduced (p<0.05). Among the eight generated subpopulations, despite the great functional heterogeneity of Th17 in SLE, a significant low proportion of Th17 producing TNF-α was found in inactive SLE, while active SLE showed a high proportion producing only IL-17. Our findings support the idea that the functional heterogeneity of Th17 cells could depend on the cytokine microenvironment, which is distinct in normal BM as well as in active SLE, probably due to a Th1/Th2 imbalance previously reported by our group.

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“…Several studies have identifi ed a subset of Th 17 cells isolated from gut mucosa of CD patients that produce IFN-along with IL-17A. 11,12 In addition, a subset of Th 17 cells isolated from the lamina propria of CD patients has been reported to express FoxP3 and exhibit suppressive activity. 6 Th erefore, there is overlap among Th 17, Th 1, and Treg cell lineages in the colonic mucosa of CD patients, and this heterogeneous population of gut Th17 cells that express IL-17A in combination with either IFN-or FoxP3 likely contains cells with diff erent, potentially opposing roles.…”

Section: Commentaries Nature Publishing Groupmentioning

confidence: 99%