A Th17‐like developmental process leads to CD8<sup>+</sup> Tc17 cells with reduced cytotoxic activity

Huber, Magdalena; Heink, Sylvia; Grothe, Henrike; Guralnik, Anna; Reinhard, Katharina; Elflein, Karin; Hünig, Thomas; Mittrücker, Hans‐Willi; Brüstle, Anne; Kamradt, Thomas; Lohoff, Michael

doi:10.1002/eji.200939412

Cited by 205 publications

(217 citation statements)

References 37 publications

(98 reference statements)

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“…STAT3 is required for IL-17 and IL-22 secretion and likely contributes to IL-17-producing T-cell expansion and/or differentiation (25,(27)(28)(29). We, therefore, investigated STAT3 activation downstream of R381Q and WT IL23R in CD8+ T cells.…”

Section: Resultsmentioning

confidence: 99%

Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses

Sarin

Abraham

2011

Proc. Natl. Acad. Sci. U.S.A.

175

124

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The SNP (c.1142G > A;p.R381Q) in the IL-23 receptor (IL23R) confers protection from multiple inflammatory diseases, representing one of the most significant human genetic polymorphisms in autoimmunity. We, therefore, sought to define the functional consequences of this clinically significant variant. We find that CD4+CD45RO+ and CD8+ T cells from healthy R381Q IL23R carriers show decreased IL-23-dependent IL-17 and IL-22 production relative to WT IL23R individuals. This was associated with a lower percentage of circulating Th17 and Tc17 cells. Furthermore, CD8+ T cells from R381Q IL23R individuals showed decreased IL-23-dependent expansion and signal transducer and activator of transcription 3 (STAT3) activation compared with WT CD8+ T cells. Importantly, cells transfected with the IL23R glutamine variant show decreased IL-23-mediated signaling compared with the IL23R arginine allele. Our results show that the R381Q IL23R variant leads to selective, potentially desirable, loss of function alterations in primary human CD4+ and CD8+ T cells, resulting in highly significant protection against autoimmunity.cytokines | Crohn's disease | ulcerative colitis | psoriasis T he IL-23/Th17 pathway is critical for optimal microbial defenses (1, 2); however, disregulation of this pathway can lead to inflammation (3-9). The SNP (c.1142G > A; p.R381Q) in IL-23 receptor (IL23R) confers protection from inflammatory diseases, including ankylosing spondylitis, psoriasis, and inflammatory bowel disease (10-12); it represents one of the most significant human genetic polymorphisms in autoimmunity. On binding to the IL23R complex, IL-23 mediates its effects by signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and NF-κB pathways (13,14). IL-23 modulates responses in multiple cell populations, including differentiation and maintenance of CD4+ Th17 (6, 15-17) and CD8+ Tc17 cells (18)(19)(20)(21).We considered that the disease-protective R381Q IL23R may result in a loss of function, leading to decreased IL-23/Th17 pathway cytokine production, or a gain of function, leading to enhanced microbial clearance. We find that CD4+CD45RO+ and CD8+ T cells from healthy R381Q IL23R carriers show decreased IL-23-dependent IL-17 and IL-22 production relative to WT IL23R individuals. This was associated with a lower percent of circulating Th17 and Tc17 cells. Furthermore, R381Q CD8+ T cells showed decreased IL-23-and STAT3-dependent expansion and STAT3 activation compared with WT cells. Our results indicate that the protective R381Q IL23R variant leads to selective loss of function in primary human CD4+ and CD8+ T cells. ResultsMemory CD4+ T Cells from R381Q IL23R Individuals Show Decreased IL-23-Mediated Th17 Cytokine Production on in Vitro Stimulation. To define the role of the disease-protective R381Q IL23R polymorphism, we genotyped 650 healthy individuals and identified 48 individuals carrying the minor glutamine allele, consistent with prior estimates of a 7% allele frequency (11). WT individuals are...

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Section: Resultsmentioning

confidence: 99%

Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses

Sarin

Abraham

2011

Proc. Natl. Acad. Sci. U.S.A.

175

124

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“…1 STAT3 is known to stabilize Tc17 phenotype. 9 Relatively more STAT3 binds to the IL-17 promoter than STAT5, regardless of whether the CTLA-4-induced Tc17 cells are re-stimulated under Tc1 conditions (Fig. 6B).…”

Section: Discussionmentioning

confidence: 92%

“…[4][5][6] Nevertheless, depending on the activation conditions, a cytokine milieu containing transforming growth factor b (TGF-b) and IL-6 7,8 drives CD8 C T cells to differentiate into IL-17-producing Tc17 cells, which have only limited cytotoxic activity. 9 In addition to TCR and co-stimulation-mediated signals, a third signal provided by cytokine receptor engagement with its respective cytokine, strongly determines the outcome of T cell differentiation as well as the stability of the initial phenotype. Cytokine engagement with its receptor induces the phosphorylation of STAT molecules, which translocate into the nucleus and bind to the promoters of their target genes.…”

Section: Introductionmentioning

confidence: 99%

“…STAT3 also induces the transcription of IL-21 and IL-23R, further increasing pSTAT3 expression and ultimately leading to stabilization of the Tc17 phenotype. 9,[11][12][13] T cells lacking STAT3 do not express the Tc17 hallmarks IL-17 and RORgt. 14 The cytokines IL-2 and IFNg, which strongly induce STAT5 and STAT1, are known to prevent the differentiation of IL-17-producing T cells.…”

Section: Introductionmentioning

confidence: 99%

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The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

et al. 2017

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As the blockade of inhibitory surface-molecules such as CTLA-4 on T cells has led to recent advances in antitumor immune therapy, there is great interest in identifying novel mechanisms of action of CD8 C T cells to evoke effective cytotoxic antitumor responses. Using in vitro and in vivo models, we investigated the molecular pathways underlying the CTLA-4-mediated differentiation of IL-17-producing CD8 C T cells (Tc17 cells) that strongly impairs cytotoxicity. Our studies demonstrate that Tc17 cells lacking CTLA-4 signaling have limited production of STAT3-target gene products such as IL-17, IL-21, IL-23R and RORgt. Upon re-stimulation with IL-12, these cells display fast downregulation of Tc17 hallmarks and acquire Tc1 characteristics such as IFNg and TNF-a co-expression, which is known to correlate with tumor control. Indeed, upon adoptive transfer, these cells were highly efficient in the antigen-specific rejection of established OVA-expressing B16 melanoma in vivo. Mechanistically, in primary and re-stimulated Tc17 cells, STAT3 binding to the IL-17 promoter was strongly augmented by CTLA-4, associated with less binding of STAT5 and reduced relative activation of STAT1 which is known to block STAT3 activity. Inhibiting CTLA-4-induced STAT3 activity reverses enhancement of signature Tc17 gene products, rendering Tc17 cells susceptible to conversion to Tc1-like cells with enhanced cytotoxic potential. Thus, CTLA-4 critically shapes the characteristics of Tc17 cells by regulating relative STAT3 activation, which provides new perspectives to enhance cytotoxicity of antitumor responses.

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“…Little is currently known about FOXP3 + CD8 + T cells; however, recent studies have suggested that these cells retain regulatory function and can express surface markers generally associated with CD4 + Treg cells such as 37]. Studies aiming at further understanding the transcriptional program that regulates the differentiation of IL-17 + and FOXP3 + CD8 + T cells both in vitro and in vivo would therefore be of interest.Importantly, Tc17 cells were found to be upregulated in many types of tumors [18][19][20], and these cells could potentially hinder antitumor immunity since Tc17 cells appear to exert less cytotoxic capacity compared to normal CD8 + T cells [38]. A recent study described that CD4 + CD25 − T cells were required to prevent the differentiation of naïve CD8 + T cells into Tc17 cells in Th17-promoting culture conditions in vitro [39].…”

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confidence: 99%

Constitutive induction of intestinal Tc17 cells in the absence of hematopoietic cell‐specific MHC class II expression

et al. 2013

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The enteric pathogen Citrobacter rodentium induces a mucosal IL-17 response in CD4 + T helper (Th17) cells that is dependent on the Nod-like receptors Nod1 and Nod2. Here, we sought to determine whether this early Th17 response required antigen presentation by major histocompatibility complex class II (MHCII) for full induction. At early phases of C. rodentium infection, we observed that the intestinal mucosal Th17 response was fully blunted in irradiated mice reconstituted with MHCII-deficient (MHCII −/− →WT) hematopoietic cells. Surprisingly, we also observed a substantial increase in the relative frequency of IL-17 + CD8 + CD4 − TCR-β + cells (Tc17 cells) and FOXP3 + CD8 + CD4 − TCR-β + cells in the lamina propria and intraepithelial lymphocyte compartment of MHCII −/− →WT mice compared with that in WT→WT counterparts. Moreover, MHCII −/− →WT mice displayed increased susceptibility, increased bacterial translocation to deeper organs, and more severe colonic histopathology after infection with C. rodentium. Finally, a similar phenotype was observed in mice deficient for CIITA, a transcriptional regulator of MHCII expression. Together, these results indicate that MHCII is required to mount early mucosal Th17 responses to an enteric pathogen, and that MHCII regulates the induction of atypical CD8 + T-cell subsets, such as Tc17 cells and FOXP3 + CD8 + cells, in vivo. Keywords:Citrobacter rodentium r FOXP3 + CD8 + r IL-17 r MHC class II r Tc17Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionInterleukin (IL)-17A (herein referred to as IL-17) is a cytokine critical for host defense against pathogens at mucosal surfaces. In the gastrointestinal tract, induction of mucosal IL-17 secretion Correspondence: Dr. Stephen E. Girardin e-mail: stephen.girardin@utoronto.ca was shown to be associated with protection against Salmonella enterica serovar Typhymurium [1], Citrobacter rodentium [2], and Helicobacter species [3]. IL-17 exerts its mucosal protection at least in part through an increase of neutrophil recruitment and neutrophil-driven defense mechanisms. In addition, IL-17 acts in concert with IL-22 to enhance epithelial innate functions, such as antimicrobial peptide secretion, mucus secretion, proliferation, and renewal [4,5].IL-17 can be secreted by a number of cell populations, including CD4 + T helper (Th17) cells, γδ T cells, innate lymphoid cells (that C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2896-2906 Immunity to infection 2897 include lymphoid tissue inducer cells) and natural killer T (NKT) cells [6][7][8][9][10][11]. In humans, Th17 cells appear to represent the major cell population that produces IL-17 in the intestine under normal conditions, whereas in mice IL-17 is mainly produced by Th17 and γδ T cells. Th17 cell differentiation is mediated by the cytokines IL-6 and TGF-β, whereas IL-23 and IL-1β contribute to the full activation of these cells [6,12,13]. In addition to the c...

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A Th17‐like developmental process leads to CD8⁺ Tc17 cells with reduced cytotoxic activity

Cited by 205 publications

References 37 publications

Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses

Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

Constitutive induction of intestinal Tc17 cells in the absence of hematopoietic cell‐specific MHC class II expression

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A Th17‐like developmental process leads to CD8+ Tc17 cells with reduced cytotoxic activity

Cited by 205 publications

References 37 publications

Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses

Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

Constitutive induction of intestinal Tc17 cells in the absence of hematopoietic cell‐specific MHC class II expression

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A Th17‐like developmental process leads to CD8⁺ Tc17 cells with reduced cytotoxic activity