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

Boniface, Katia; Blumenschein, Wendy M.; Brovont-Porth, Katherine; McGeachy, Mandy J.; Basham, Beth; Desai, Bela; Pierce, Robert H.; McClanahan, Terrill K.; Sadekova, Svetlana; Malefyt, René de Waal

doi:10.4049/jimmunol.1000366

Cited by 172 publications

(144 citation statements)

References 60 publications

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“…Indeed, it has been suggested in recent publications that Th17 cells expressing IFN-g have pro-inflammatory properties clearly distinct from Th1 or Th17 cells. Th1/Th17 cells could more efficiently induce the expression of inflammatory mediators on epithelial cells [44] and were found to preferentially accumulate in the CNS of MS-infected patients and EAE mice compared with IFN-g or IL-17 single producers [45]. …”

Section: Discussionmentioning

confidence: 99%

IFN‐γ and IL‐12 synergize to convert in vivo generated Th17 into Th1/Th17 cells

et al. 2010

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Th1 and Th17 cells are distinct lineages of effector/memory cells, imprinted for reexpression of , by upregulated expression of T-bet and retinoic acid-related orphan receptor ct (RORct) , respectively. Apparently, Th1 and Th17 cells share tasks in the control of inflammatory immune responses. Th cells coexpressing IFN-c and IL-17 have been observed in vivo, but it remained elusive, how these cells had been generated and whether they represent a distinct lineage of Th differentiation. It has been shown that ex vivo isolated Th1 and Th17 cells are not interconvertable by TGF-b/IL-6 and IL-12, respectively. Here, we show that ex vivo isolated Th17 cells can be converted into Th1/Th17 cells by combined IFN-c and IL-12 signaling. IFN-c is required to upregulate expression of the IL-12Rb2 chain, and IL-12 for Th1 polarization. These Th1/Th17 cells stably coexpress RORct and T-bet at the single-cell level. Our results suggest a molecular pathway for the generation of Th1/Th17 cells in vivo, which combine the pro-inflammatory potential of Th1 and Th17 cells. IntroductionTh1 cells, with a memory for IFN-g expression and determined by the master transcription factor T-bet, are considered to be essential for protection against intracellular pathogens, and had been viewed as the major pathogenic drivers of chronic autoimmune inflammation, e.g. EAE [1][2][3], uveitis [4] or colitis [5]. Recently, Th17 cells, with a memory for expression of IL-17 and determined by the transcription factor retinoic acid related orphan receptor gt (RORgt), have been identified as another pathogenic Th-cell lineage driving pathogenesis in these autoimmune models [6,7]. Th17 cells contribute to inflammation through the recruitment of neutrophils and the induction of secretion of pro-inflammatory mediators such as IL-6, IL-8, TNF-a, IL-1b, CXCL1, CXCL10 and matrix metalloproteinases from tissue cells (reviewed in [8]). Th1 cells contribute to inflammation by activation of macrophages [9]. The concerted action of IFN-g and IL-17 has been shown to be essential in the effective induction and maintenance of autoimmunity [10,11], e.g. Th1 cells being required for the recruitment of Th17 cells into the central nervous system in EAE.In inflamed tissue of autoimmune patients, Th cells coexpressing IFN-g and IL-17 have been identified [12][13][14].Ã These authors have contributed equally to this study. ResultsIn vivo, Th17 cells do not express IL-12Rb2 and do not respond to IL-12Although IL-17-expressing cells isolated from cultures stimulated in vitro respond to subsequent stimulation with IL-12 with gain of IFN-g expression and loss of IL-17 expression (Fig. 1A, upper panel), IL-17 expressing cells directly isolated ex vivo maintained IL-17 expression and could not be induced to express IFN-g in the presence of IL-12 (Fig. 1A, lower panel) [17,19]. To identify the molecular mechanism of refraction of in vivo generated Th17 cells to conversion by IL-12, we here compared the expression of genes relevant for IL-12 signaling by Th17 cells generated in vit...

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Section: Discussionmentioning

confidence: 99%

IFN‐γ and IL‐12 synergize to convert in vivo generated Th17 into Th1/Th17 cells

et al. 2010

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“…Th17 cells may convert to Th1 cells under inflammatory conditions (e.g., IL-12, IL-23) and may further contribute to inflammation also in humans, for example in arthritis (32,34). These "plastic" Th17 → Th1 cells have been described to maintain some features of Th17 cells, such as CD161 expression.…”

Section: Discussionmentioning

confidence: 99%

Human Th17 Cells Express High Levels of Enzymatically Active Dipeptidylpeptidase IV (CD26)

Bengsch

Seigel

Flecken

et al. 2012

The Journal of Immunology

157

163

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Dipeptidylpeptidase IV (CD26) is a multifunctional ectoenzyme involved in T cell activation that has been implicated in autoimmune pathophysiology. Because IL-17–producing CD4+ T cells (Th17 cells) are important mediators of autoimmune disease, we analyzed the expression of CD26 and its enzymatic function on human Th17 cells. Analysis of CD26 expression on different CD4+ T helper subsets showed that CD26 expression is highest on CD4+ T cells producing type 17 cytokines (e.g., IL-22, IL-17, GM-CSF, or TNF) compared with Th1, Th2, and regulatory T cells. Phenotypic analysis revealed that CD26++CD4+ T cells express the type 17 differentiation molecules CD161, CCR6, lL-23R, and retinoic acid-related orphan receptor-γt. Furthermore, sorted CD26++CD4+ T cells contain >90–98% of Th17 cells, indicating that CD26++ T cells harbor the Th17 lineage. A comparison with CD161 and CCR6 indicated that analysis of CD26 coexpression may improve the phenotypic characterization of Th17 cells. Of note, CD26++ Th17 cells are enriched in the inflamed tissue of patients with hepatitis and inflammatory bowel disease. Functional analysis in migration assays revealed that CD26 expressed on Th17 cells is enzymatically active. Indeed, CD26 negatively regulates the chemotactic CD4+ T cell response to the inflammatory chemokines CXCL9–12 that can be restored by pharmacological blockade of the enzymatic center of CD26. In summary, these results strongly suggest that CD26 may contribute to the orchestration of the immune response by Th17 cells in human inflammatory diseases. They also suggest that the phenotypic analysis of Th17 cells may be facilitated by determination of CD26 expression.

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“…These IFN-c/IL-17 double-producing cells are found in both mice and humans, often associated with infection or isolated from sites of inflammation. 68,[76][77][78][79][80] 81,82 in certain situations acquiring the ability to secrete additional cytokines (e.g. IFN-c).…”

Section: Th17 Cells a Heterogeneous And Plastic Populationmentioning

confidence: 99%

“…Instead, Th17 cells are a heterogeneous population containing a number of different subpopulations expressing different combinations of Th17-type cytokines. 40,68 The cytokine profile of an individual Th17 cell is likely to be influenced by the local environment during T-cell priming. 74 Th17 cells have also been shown to produce TNF-a and IL-6, 15 and one study has reported the expression of IL-10 by Th17 cells generated with TGF-b and IL-6, a phenotype not observed when cells were expanded with IL-23.…”

Section: Th17 Cells a Heterogeneous And Plastic Populationmentioning

confidence: 99%

“…84 Interleukin-12 has been reported to down-regulate IL-17 expression and induce switching to IFN-c production also in human Th17 populations, both in Th17 clones 78 and in in vitroderived Th17 and IFN-c + IL-17A + cells. 68 Third, the transition from Th17 cells to IFN-c-producing cells requires signal transducer and activator of transcription 4 (STAT4) and T-bet, 84 factors that are up-regulated following culture of Th17 populations with IL-12. 84,85,88,92 Experiments have also been performed to analyse the phenotype stability of in-vitro-generated Th17 cells following in vivo transfer.…”

Section: Th17 Cells a Heterogeneous And Plastic Populationmentioning

confidence: 99%

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Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity

2011

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Summary Interleukin‐23 (IL‐23) plays an essential role in driving intestinal pathology in experimental models of both T‐cell‐dependent and innate colitis. Furthermore, genome‐wide association studies have identified several single‐nucleotide polymorphisms in the IL‐23 receptor (IL‐23R) gene that are associated with either susceptibility or resistance to inflammatory bowel disease in humans. Although initially found to support the expansion and maintenance of CD4+ T helper 17 (Th17) cells, IL‐23 is now recognized as having multiple effects on the immune response, including restraining Foxp3+ regulatory T‐cell activity and inducing the expression of Th17‐type cytokines from non‐T‐cell sources. Here we focus on Th17 cells and their associated cytokines IL‐17A, IL‐17F, IL‐21 and IL‐22. We review studies performed in mouse models of colitis where these effector cytokines have been shown to have either a pathogenic or a tissue‐protective function. We also discuss the heterogeneity found within the Th17 population and the phenomenon of plasticity of Th17 cells, in particular the ability of these lymphocytes to extinguish IL‐17 expression and turn on interferon‐γ production to become Th1‐like ‘ex‐Th17’ cells. Interleukin‐23 has been identified as a key driver in this process, and this may be an additional mechanism by which IL‐23 promotes pathology in the intestinal tract. These ‘ex‐Th17’ cells may contribute to disease pathogenesis through their secretion of pro‐inflammatory mediators.

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

Cited by 172 publications

References 60 publications

IFN‐γ and IL‐12 synergize to convert in vivo generated Th17 into Th1/Th17 cells

IFN‐γ and IL‐12 synergize to convert in vivo generated Th17 into Th1/Th17 cells

Human Th17 Cells Express High Levels of Enzymatically Active Dipeptidylpeptidase IV (CD26)

Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity

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