Identification of CD25+ γδ T Cells As Fetal Thymus-Derived Naturally Occurring IL-17 Producers

Shibata, Kensuke; Yamada, Hisakata; Nakamura, Ryô; Sun, Xun; Itsumi, Momoe; Yoshikai, Yasunobu

doi:10.4049/jimmunol.181.9.5940

Cited by 164 publications

(216 citation statements)

References 46 publications

(47 reference statements)

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“…IL-17 + γδ T lymphocytes are committed as IL-17 producers within the fetal thymus, via RORγt transcriptional factor-and NotchHes1-dependent mechanisms, independently of TCR signaling [43][44][45][46] and CD27 costimulation [47]. In the immune site, their activation is determined by multiple cytokines, among which a chief role is attributed to IL-1β and IL-23 in mice and humans [48][49][50].…”

Section: Discussionmentioning

confidence: 99%

CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

Costa¹,

Bornstein²,

Candéa³

et al. 2012

Eur J Immunol

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Herein, we provide evidence that during allergic inflammation, CCL25 induces the selective migration of IL-17 + γδ T cells mediated by α 4 β 7 integrin. Intrapleural injection of CCL25 into ovalbumin (OVA)-immunized C57BL/6 mice triggered the accumulation of γδ T lymphocytes expressing CCR9 (CCL25 receptor) and α 4 β 7 integrin in the pleura, but failed to attract αβ T lymphocytes. CCL25 attracted CCR6 + γδ T cells producing IL-17 (but not IFN-γ or IL-4). OVA challenge triggered increased production of CCL25 followed by the accumulation of CCR9 + , α 4 β 7 + , and CCR6 + /IL-17 + γδ T cells into the pleural cavities of OVA-immunized mice, which was inhibited by the in vivo neutralization of CCL25. The in vivo blockade of α 4 β 7 integrin also inhibited the migration of IL-17 + γδ T lymphocytes (but not of αβ T lymphocytes) into mouse pleura after OVA challenge, suggesting that the CCL25/α 4 β 7 integrin pathway is selective for γδ T cells. In addition, α 4 β 7 integrin blockade impaired the in vitro transmigration of γδ T cells across endothelium (which expresses α 4 β 7 ligands VCAM-1 and MadCAM-1), which was induced by CCL25 and by cell-free pleural washes recovered from OVA-challenged mice. Our results reveal that during an allergic reaction, CCL25 drives IL-17 + γδ T-cell mobilization to inflamed tissue via α 4 β 7 integrin and modulates IL-17 levels. Keywords: Adhesion molecules IntroductionLymphocytes bearing the γδ T-cell receptor (TCR) comprise a minor T-lymphocyte subset in blood and secondary lymphoid tissues and are preferentially localized in epithelial and mucosal tissues [1,2]. This unique subset of lymphocytes can provide rapid tissue-specific immune responses, without the requirement of antiCorrespondence: Dr. Carmen Penido e-mail: cpenido@far.fiocruz.br gen presentation or clonal expansion, and is able to produce a large repertory of Th1-, Th2-, and Th17-associated cytokines [2][3][4][5][6]. These characteristics make γδ T cells a crucial first line of defense during infection, tissue damage, or stress.γδ T cells have been shown to migrate into the airways during allergic inflammation highly controlled by a chemotactic gradient of chemokines produced in tissue [5,[7][8][9][10][11]. We have previously demonstrated that allergen-induced γδ T-cell accumulation is * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1250-1260 Immunomodulation 1251 paralleled with a marked production of chemokines in the tissue, including CCL25/TECK [11]. CCL25 is mostly described as a homeostatic chemokine that plays a major role in T-cell development in the thymus and in intraepithelial lymphocytes (IELs) homing into small intestine mucosa [12]. Recent data have provided evidence that CCL25 production increases during inflammatory processes that take place at nonmucosal tissues, such as autoimmune arthritis, atherosclerosis, and allergy [11,13,14]. Moreover, we and others have shown that γδ T lymphocytes migrate in vitro toward CCL25, via its counterpart receptor CCR9 [11,...

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Section: Discussionmentioning

confidence: 99%

CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

Costa¹,

Bornstein²,

Candéa³

et al. 2012

Eur J Immunol

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“…It is possible that the TCR Vg4 or Vg6 recognize some self-Ag induced by stress of mycobacterial infection. Alternatively, the expression of IL-17A is determined in the course of TCR gd T cells development irrelevant to infection (47). Further information on the recognition mechanism of the IL-17A-producing TCR gd T cells would give important information on regulation of the IL-17A-producing TCR gd T cells to protect the host from M. tuberculosis infection.…”

Section: Discussionmentioning

confidence: 99%

Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung

Yoshida

Umemura

Yahagi

et al. 2010

The Journal of Immunology

348

261

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Granulomas play an essential role in the sequestration and killing of mycobacteria in the lung; however, the mechanisms of their development and maturation are still not clearly understood. IL-17A is involved in mature granuloma formation in the mycobacteria-infected lung. Therefore, IL-17A gene-knockout (KO) mice fail to develop mature granulomas in the Mycobacterium bovis bacille Calmette-Guérin (BCG)-infected lung. This study analyzed the mechanism of IL-17A–dependent mature granuloma formation in the mycobacteria-infected lung. The IL-17A KO mice showed a normal level of nascent granuloma formation on day 14 but failed to develop mature granulomas on day 28 after the BCG infection in the lung. The observation implies that IL-17A is required for the maturation of granuloma from the nascent to mature stage. TCR γδ T cells expressing TCR Vγ4 or Vγ6 were identified as the major IL-17A–producing cells that resided in the BCG-induced lung granuloma. The adoptive transfer of the IL-17A–producing TCR γδ T cells reconstituted granuloma formation in the IL-17A KO mice. The expression of ICAM-1 and LFA-1, which are adhesion molecules important in granuloma formation, decreased in the lung of the BCG-infected IL-17A KO mice, and their expression was induced on BCG-infected macrophages in coculture with IL-17A–producing TCR γδ T cells. Furthermore, IL-17A KO mice showed not only an impaired mature granuloma formation, but also an impaired protective response to virulent Mycobacterium tuberculosis. Therefore, IL-17A produced by TCR γδ T cells plays a critical role in the prevention of M. tuberculosis infection through the induction of mature granuloma formation.

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“…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: 98%

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

Akitsu

Iwakura

2018

Immunology

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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.

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Identification of CD25+ γδ T Cells As Fetal Thymus-Derived Naturally Occurring IL-17 Producers

Cited by 164 publications

References 46 publications

CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung

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

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Identification of CD25+ γδ T Cells As Fetal Thymus-Derived Naturally Occurring IL-17 Producers

Cited by 164 publications

References 46 publications

CCL25 induces α4β7 integrin‐dependent migration of IL‐17+γδ T lymphocytes during an allergic reaction

CCL25 induces α4β7 integrin‐dependent migration of IL‐17+γδ T lymphocytes during an allergic reaction

Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung

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

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CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction