CD27 is a thymic determinant of the balance between interferon-γ- and interleukin 17–producing γδ T cell subsets

Ribot, Julie C.; deBarros, Ana; Pang, Dick John; Neves, Joana F.; Peperzak, Victor; Roberts, Scott; Girardi, Michael; Borst, Jannie; Hayday, Adrian; Pennington, Daniel J.; Silva‐Santos, Bruno

doi:10.1038/ni.1717

Cited by 557 publications

(814 citation statements)

References 51 publications

Supporting

Mentioning

760

Contrasting

Unclassified

Order By: Relevance

“…S1D). Notably, regardless of exposure to Dll4, the KN6 cells maintained high CD27 expression, a phenotype that is associated with IFNγ-producing γδ T cells 31 (Fig. S1D).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Zarin

Chen

et al. 2018

Immunol Cell Biol

View full text Add to dashboard Cite

γδ T-cells perform a wide range of tissue and disease specific functions that are dependent on the effector cytokines produced by these cells. However, the aggregate signals required for the development of interferon-γ (IFNγ) and interleukin-17 (IL-17) producing γδ T-cells remain unknown. Here, we define the cues involved in the functional programming of γδ T-cells, by examining the roles of T-cell receptor (TCR), Notch, and cytokine-receptor signaling. KN6 γδTCR-transduced Rag2−/− T-cell progenitors were cultured on stromal cells variably expressing TCR and Notch ligands, supplemented with different cytokines. We found that distinct combinations of these signals are required to program IFNγ versus IL-17 producing γδ T cell subsets, with Notch and weak TCR ligands optimally enabling development of γδ17 cells in the presence of IL-1β, IL-21 and IL-23. Notably, these cytokines were also shown to be required for the intrathymic development of γδ17 cells. Together, this work provides a framework of how signals downstream of TCR, Notch and cytokine receptors integrate to program the effector function of IFNγ and IL-17 producing γδ T-cell subsets.

show abstract

“…S1D). Notably, regardless of exposure to Dll4, the KN6 cells maintained high CD27 expression, a phenotype that is associated with IFNγ-producing γδ T cells 31 (Fig. S1D).…”

Section: Resultsmentioning

confidence: 99%

“…γδ17 cells are characterized by high levels of CD44 and low levels of CD62L and CD27 31 . We therefore assessed the expression of these cell surface markers in control (+IL-7) versus CK supplemented cultures.…”

Section: Resultsmentioning

confidence: 99%

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Zarin

Chen

et al. 2018

Immunol Cell Biol

View full text Add to dashboard Cite

show abstract

“…Although IL‐23R is constitutively expressed on γδ 17 cells, the expression of IL‐1R in peripheral γδ 17 cells is tissue‐dependent 48. In addition to IL‐1R and IL‐23R, the expression of scavenger receptor 2 (Scart 2)49 and CCR6,27 and the lack of CD12225 and CD27 expression26 are often used as markers for γδ 17 cells, with the exception for IL‐17‐producing V γ 1 + γδ T cells 33. These phenotypes, established during thymic development, distinguish γδ 17 cells from IFN‐γ‐producing γδ T ( γδ IFN‐ γ ) cells (Fig.…”

Section: γδ T‐cell Subsets and Their Developmentmentioning

confidence: 99%

“…To induce IL‐17, naive T cells have to differentiate into Th17 cells in the periphery by the stimulation with T‐cell receptor (TCR) and cytokines such as IL‐6 and transforming growth factor‐ β . In contrast, the functional potential to produce IL‐17 in γδ 17 cells is already established during intra‐thymic development25, 26, 27 and IL‐17 is directly induced by IL‐23 and IL‐1 without TCR stimulation in the periphery. This pre‐programming contributes to rapid IL‐17 production in peripheral tissues in the early phase of pathogen infection.…”

Section: Introductionmentioning

confidence: 99%

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Akitsu

Iwakura

2018

Immunology

View full text Add to dashboard Cite

SummaryInterleukin‐17 (IL‐17) is a pro‐inflammatory cytokine and is involved in the development of many diseases. Recent studies have revealed that IL‐17‐producing γδ T cells (γδ17 cells) in addition to IL‐17‐producing CD4+ T cells [T helper type 17 (Th17) cells] are often the main producers of IL‐17 in mouse models of inflammatory diseases. γδ T cells are functionally committed during intra‐thymic differentiation. γδ thymocytes capable of producing IL‐17, which express the transcription factor retinoic‐acid‐receptor‐related orphan receptor γt and the signature cytokine receptor IL‐23R, leave the thymus, and produce IL‐17 rapidly by the stimulation with IL‐1β and IL‐23 in the periphery. Therefore, γδ17 cells play important roles in the early phase of host defence against pathogens and in inflammatory diseases. γδ T cells that can produce IL‐17 are also increased in the skin of patients with psoriasis and in peripheral blood of patients with ankylosing sclerosis. Indeed, the therapy targeting IL‐17 has been approved or is in clinical trials, and proved to be very efficient to treat psoriasis, psoriatic arthritis and ankylosing sclerosis. In this review, we discuss recent knowledge about the pathophysiological function of γδ17 cells in infection and inflammatory diseases and therapeutic advances targeting IL‐17.

show abstract

“…3B). These findings suggest that circulating gd T cells but not skin resident gd T cells migrated into the tumor tissues.Recently, IL-17-producing gd T cells have been defined as a CD27 À CCR6 1 gdTCR 1 population [36][37][38]. Accordingly, we analyzed the expression of these markers on IL-17-producing TIL and found that IL-17-producing gd T cells did not express the CD27 molecule; however, both CCR6 1 and CCR6 À gd T cells produced IL-17 in the tumor site (Fig.…”

mentioning

confidence: 94%

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

et al. 2010

View full text Add to dashboard Cite

Based on the evidence that IL-17 is a key cytokine involved in various inflammatory diseases, we explored the critical role of IL-17-producing cd T cells for tumor development in tumor-bearing mouse model. IL-17 À/À mice exhibited a significant reduction of tumor growth, concomitantly with the decrease of vascular density at lesion area, indicating a pro-tumor property of IL-17. Among tumor-infiltrating lymphocytes (TIL), cd T cells were the major cellular source of IL-17. Analysis of TCR repertoires in TIL-cd T cells showed that circulating cd T cells, but not skin resident Vc5 1 cd T cells, produced IL-17. Neutralizing antibodies against IL-23, IL-6, and TGF-b, which were produced within the tumor microenvironment, inhibited the induction of IL-17-producing cd T cells. IL-17 production by tumor-infiltrating cd T cells was blocked by anti-cdTCR or anti-NKG2D antibodies, indicating that these ligands, expressed within the tumor microenvironment, are involved in cd T-cell activation. The IL-17-producing TIL-cd T cells exhibited reduced levels of perforin mRNA expression, but increased levels of COX-2 mRNA expression. Together, our findings support the novel concept that IL-17-producing cd T cells, generated in response to tumor microenvironment, act as tumor-promoting cells by inducing angiogenesis. IntroductionIn order to understand how tumor cells can escape immune surveillance mechanisms and thus develop anti-tumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. The tumor microenvironment, which is mainly composed of tumor cells, stromal cells, and tumor-infiltrating immune cells, is entirely different from noncancerous tissues. This unique microenvironment potently inhibits immune responses against tumor cells via various soluble mediators and contact-dependent mechanisms [1,2]. Previously, it was suggested that T-cell Eur. J. Immunol. 2010. 40: 1927-1937 DOI 10.1002 Cellular immune response 1927 responses within the local tumor tissue are completely inhibited. However, this concept was abandoned following the discovery of the regulatory T-cell and Th17 cell subsets, which are activated rather than suppressed in the tumor microenvironment via TGF-b and/or IL-6. Thus, the tumor microenvironment is conducive to IL-17 production. In fact, it has been shown that IL-17 is produced in human and murine tumor tissues [3][4][5]. Tumor cells promote neo-vascularization into tumor tissues through hyperproduction of angiogenic factors, which also support their own abnormal proliferation and survival [6]. It has been reported that tumor cells over-expressing IL-17 significantly promote new vessel growth into the tumor tissues [5]; however, physiological effects of IL-17 on tumor progression remain to be defined. Th17 differentiation from naïve CD4 1 T cells is regulated by TGF-b and IL-6. Proliferation, maintenance and full maturation of these cells are controlled by . Recently, it has been shown that IL-17 is produced by diverse T...

show abstract

CD27 is a thymic determinant of the balance between interferon-γ- and interleukin 17–producing γδ T cell subsets

Cited by 557 publications

References 51 publications

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

Contact Info

Product

Resources

About