Human interleukin 17–producing cells originate from a CD161+CD4+ T cell precursor

Cosmi, Lorenzo; Palma, Raffaele De; Santarlasci, Veronica; Maggi, Laura; Capone, Manuela; Frosali, Francesca; Rodolico, Gabriella; Querci, Valentina; Abbate, Gianfranco; Angeli, Roberta; Berrino, Liberato; Fambrini, Massimiliano; Caproni, Marzia; Tonelli, Francesco; Lazzeri, Elena; Parronchi, Paola; Liotta, Francesco; Maggi, Enrico; Romagnani, Sergio; Annunziato, Francesco

doi:10.1084/jem.20080397

Cited by 644 publications

(843 citation statements)

References 49 publications

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“…6D). Finally, we assessed whether IL-22 single-positive cells generated in vitro from naïve T cells expressed CD161, a marker reported to be specific of Th17 cells [9,36]. Our results confirm the strong expression of CD161 by most IL-17 1 IL-22 À IFN-g À cells but also show that CD161 is virtually absent from IL-22 1 IL-17A À IFN-g À single-positive T cells (Fig.…”

supporting

confidence: 70%

“…Fifth, priming of CD4 1 naïve T cells in the presence of TCDD resulted in increased number of IL-22 1 IL-17 À IFN-g À single-positive T cells. Finally, CD161 selectively expressed in Th17 cells [9,36] was absent in IL-22 1 IL-17A À IFN-g À singlepositive T cells. Furthermore, our data regarding the dissociated IL-22 and IL-17 production are consistent with recent reports showing that skin-homing memory T cells [31,32], T cells present in the skin of individuals affected by atopic dermatitis [41], plaque psoriasis, allergic contact dermatitis [33] and T cells responding to mycobacteria [42] or Candida albicans [43] produce IL-22 but not IL-17A or IFN-g. Of interest, human Langerhans cells appear to favor the induction of CD4 1 T cells producing IL-22 but not IL-17, thus stressing a preferential role of these cells in skin immunosurveillance [44].…”

Section: Discussionmentioning

confidence: 91%

“…Th17 cells are expanded and terminally differentiated in the presence of IL-23 [2]. Human Th17 cells may be generated in the presence of IL-1 and IL-23; IL-1 and IL-6; or TGF-b and IL-21 [7][8][9][10]. Th17 cells express CCR6 and produce the CCR6-ligand CCL20, thereby amplifying Th17 cell recruitment at sites of inflammation [11].…”

Section: Introductionmentioning

confidence: 99%

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Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

Ramirez¹,

Brembilla²,

Sorg³

et al. 2010

Eur J Immunol

163

141

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Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo [3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-c, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4 1 T cells. The specific AHRinhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4 1 T cells to produce IL-22 without IL-17 and IFN-c. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161 1 Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4 1 T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage. IntroductionLocal cytokine milieu during antigen presentation profoundly affects the differentiation program of CD4 1 T cells [1]. In the mouse, TGF-b, in the presence of IL-6 and pro-inflammatory cytokines, favors the emergence of Th17 cells that produce IL-17 and express the master transcription factor retinoic acid-related orphan receptor (ROR)gt [2][3][4][5][6]. Th17 cells are expanded and terminally differentiated in the presence of . Human Th17 cells may be generated in the presence of IL-1 and IL-23; IL-1 and IL-6; or . Th17 cells express CCR6 and 2450produce the CCR6-ligand CCL20, thereby amplifying Th17 cell recruitment at sites of inflammation [11]. IL-22, a member of the IL-10-family, is produced by Th17 cells, and to some extent by Th1 cells, NKT cells, NK cells and lymphoid tissue inducer-like cells [12]. IL-22 signals via a receptor consisting of IL-22R and IL-10R2 subunits [11]. Cells of hemapoietic origin do not express IL-22R; instead, IL-2R is highly expressed by epithelial cells of the gastrointestinal tract and the skin. In the mouse, IL-23 was shown to drive preferential expansion of cells that co-express IL-22 and IL-17, that may synergize to augment the expression of genes involved in defense against microbial pathogens [13,14]. However, several mouse models of infection and autoimmunity suggested distinct roles for .In addition to cytokines, other mediators may impact CD4 1 T-cell differentiation. We and others have shown that prostaglandin E2 (PGE2) favors human Th17 expansion [20][21][22]. Furthermore, ligands of the aryl hydrocarbon receptor (AHR) exert a role. AHR is a...

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supporting

confidence: 70%

Section: Discussionmentioning

confidence: 91%

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Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

Ramirez¹,

Brembilla²,

Sorg³

et al. 2010

Eur J Immunol

163

141

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“…76 CD161 expression by T lymphocytes has also been linked to their capacity to secrete IL-17A. 77 MDR1 expression might therefore be required for their proper function and to preserve them from toxins and xenobiotics particularly abundant in the intestine. In this matter, a recent work from Cao et al .…”

Section: Introductionmentioning

confidence: 99%

MDR1 in immunity: friend or foe?

et al. 2018

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MDR1 is an ATP-dependent transmembrane transporter primarily studied for its role in the detoxification of tissues and for its implication in resistance of tumor cells to chemotherapy treatment. Several studies also report on its expression on immune cells where it plays a protective role from xenobiotics and toxins. This review provides an overview of what is known on MDR1 expression in immune cells in human, and its implications in different pathologies and their treatment options.

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“…We have also shown that virtually all human memory Th17 cells are contained within the CD161 + fraction of both circulating and tissue-infiltrating CD4 + T cells, and originate from CD161 + precursors present in umbilical cord blood and newborn thymus [9]. In humans, Th1 cells that derive from the shifting of Th17 cells have been defined as nonclassic Th1 cells [8,10], since they can be distinguished from classic Th1 cells by the expression of CD161, as expressed by Th17 cells [9][10][11].More recently, we have demonstrated that Th17 cells, unlike classic Th1 cells, do not proliferate in response to anti-CD3 plus anti-CD28 mAb stimulation; this unresponsiveness is due mainly to the inability of human Th17 cells to produce IL-2, which could be related to their reduced c-Fos, c-Jun, and NFAT activity [12]. Moreover, we found that the reduced activity of these transcription factors is associated with high expression of IL-4-induced gene 1 (IL4I1) mRNA, which encodes an L-phenylalanine oxidase able to downregulate the expression of CD3 chains in T cells, thus resulting in a poor ability to expand in response to TCR stimulation [12].…”

mentioning

confidence: 96%

IL‐4‐induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells

et al. 2013

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Human Th17 cells have a limited proliferative capacity compared to other T-cell subsets.We have shown that human Th17 cells display impaired IL-2 production due to IL-4-induced gene 1 (IL4I1) upregulation. Here, we show that in human Th17 cells, IL4I1 also maintains high levels of Tob1, a member of the Tob/BTG (B-cell traslocation gene) antiproliferative protein family, which prevents cell-cycle progression mediated by TCR stimulation. Indeed, Th17 cells exhibited higher levels of Tob1 than Th1 cells in both resting and TCR-activated conditions. Accordingly, the expression of positive regulators of the cell cycle (cyclin A, B, C, and E and Cdk2), as well as of Skp2, which promotes Tob1 degradation, was lower in Th17 cells than in Th1 cells. Tob1 expression in human Th17 cells correlated with both RAR (retinoic acid receptor)-related orphan receptor C (RORC) and IL4I1 levels. However, RORC was not directly involved in the regulation of Tob1 expression, whereas IL4I1 silencing in Th17 cells induced a substantial decrease of Tob1 expression. These data suggest that IL4I1 upregulation in human Th17 cells limits their TCR-mediated expansion not only by blocking the molecular pathway involved in the activation of the IL-2 promoter, but also by maintaining high levels of Tob1, which impairs entry into the cell cycle. Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Francesco Annunziato e-mail: francesco.annunziato@unifi.it * These authors equally contributed to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 654-661 HIGHLIGHTS 655 IntroductionActivated CD4 + T cells can be subdivided into lineages on the basis of their cytokine production, their specific transcription factor expression and their immunological function: T helper type 1 (Th1) cells express the transcription factor T-box expressed in T cells, secrete IFN-γ, and protect the host against intracellular infections; Th2 cells express the transcription factor GATA-3, secrete IL-4, IL-5, and IL-13, and mediate host defense against helminths; Th17 cells selectively produce IL-17A, express the transcription factor retinoic acid receptor (RAR) related orphan receptor γt, and are critical for the host's defense against extracellular pathogens [1][2][3][4]. Moreover, a subset of human IL-17A-producing CD4 + T cells was found to also produce IFN-γ (Th17/Th1) and both Th17 and Th17/Th1 cells exhibit plasticity toward the Th1 profile when cultured in the presence of . Similar findings were also reported in some murine models [5][6][7] suggesting that both human and murine Th17 cells probably represent a transient phenotype [8]. We have also shown that virtually all human memory Th17 cells are contained within the CD161 + fraction of both circulating and tissue-infiltrating CD4 + T cells, and originate from CD161 + precursors present in umbilical cord blood and newborn thymus [9]. In humans, Th1 cells that derive from the shif...

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Human interleukin 17–producing cells originate from a CD161+CD4+ T cell precursor

Abstract: We demonstrate that CD161 is a highly up-regulated gene in human interleukin

Cited by 644 publications

References 49 publications

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

MDR1 in immunity: friend or foe?

IL‐4‐induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells

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