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Involvement of IL-17A-producing TCR γδ T cells in late protective immunity against pulmonary Mycobacterium tuberculosis infection.

ABSTRACT: Interleukin (IL)-17A is a cytokine originally reported to induce neutrophil-mediated inflammation and anti-microbial activity. The CD4(+) T cells, which produce IL-17A, have been well characterized as Th17 cells. On the other hand, IL-17A-producing TCR γδ(+) T cells have been reported to participate in the immune response at an early stage of infection with Listeria monocytogenes and Mycobacterium bovis in mice. However, the involvement of IL-17A in protective immunity was not clearly demonstrated in the chronic stage of M. tuberculosis-infected mice.We analyzed role of IL-17A in host defense against chronically infected M. tuberculosis using IL-17A KO mice.We found that TCR γδ(+) T cells are a primary source of IL-17A, but that mycobacterial antigen-specific Th17 cells were hardly detected even at the chronic stage of M. tuberculosis infection. IL-17A-deficient mice showed a decreased survival rate, and increased bacterial burden in the lungs after the infection when compared to the wild-type mice. Furthermore, a histological analysis showed an impaired granuloma formation in the infected lungs of IL-17A-deficient mice, which was considered to be due to a decrease of IFN-γ and TNF at the chronic stage.Our data suggest that the IL-17A-producing TCR γδ(+) T cells, rather than the Th17 cells, in the infected lungs are an indispensable source of protective immunity against M. tuberculosis infection.

SUBMITTER: Umemura M

PROVIDER: S-EPMC5134718 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other

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Th17 cells are not required for maintenance of IL-17A-producing γδ T cells in vivo.

Project description:γδ T cells producing interleukin-17A (γδT17) are thought to develop spontaneously in the thymus and to be maintained in the periphery. Previous studies suggested a role for T-helper 17 (Th17) cells in the maintenance of γδT17 via the expression of transforming growth factor-β1 (TGFβ1). However, we have previously found that Th17 cells were not required for expansion of γδT17 cells after lung transplant in a mouse model. Using mice deficient in signal transducer and activator of transcription 3 (STAT3) in CD4+ T cells, which are unable to develop Th17 cells, we investigated the requirement for Th17 cells and TGFβ1 to maintain γδT17 cells in the lung and lymphoid tissues. At steady state, we found no defect in γδT17 cells in the thymus or periphery of these mice. Further, STAT3-deficient CD4+ T cells produced significantly higher levels of TGFβ1 than wild-type CD4+ T cells under Th17 differentiation conditions in vitro. To determine whether STAT3-deficient CD4+ T cells could expand γδT17 cells in vivo, we used TCRβ-/- mice, which are known to have a defect in γδT17 cells that can be rescued by Th17 cells. However, adoptive transfer of wild-type Th17 cells or bulk CD4+ T cells did not expand γδT17 cells in TCRβ-/- mice. In contrast, interferon-γ+ γδ T cells preferentially expanded, particularly in the lungs. Interestingly, we found in vivo and in vitro that TGFβ1 may negatively regulate the pool of γδT17 cells. Our data suggest that Th17 cells and TGFβ1 are not required for the maintenance of γδT17 cells.

| S-EPMC5360492 | biostudies-literature

Increased Production of IL-17A-Producing γδ T Cells in the Thymus of Filaggrin-Deficient Mice.

Project description:Mutations in the filaggrin gene (Flg) are associated with increased systemic levels of Th17 cells and increased IL-17A production following antigen exposure in both humans and mice. In addition to Th17 cells, γδ T cells can produce IL-17A. The differentiation of γδ T cells to either IFNγ or IL-17A-producing (γδT17) cells is mainly determined in the thymus. Interestingly, it has been reported that filaggrin is expressed in the Hassall bodies in the human thymic medulla. However, whether filaggrin affects γδ T cell development is not known. Here, we show that filaggrin-deficient flaky tail (ft/ft) mice have an increased number of γδT17 cells in the spleen, epidermis, and thymus compared to wild-type (WT) mice. We demonstrate that filaggrin is expressed in the mouse thymic medulla and that blocking the egress of cells from the thymus results in accumulation of Vγ2+ γδT17 cells in the thymus of adult ft/ft mice. Finally, we find increased T cell receptor expression levels on γδ T cells and increased levels of IL-6 and IL-23 in the thymus of ft/ft mice. These findings demonstrate that filaggrin is expressed in the mouse thymic medulla and that production of Vγ2+ γδT17 cells is dysregulated in filaggrin-deficient ft/ft mice.

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PD-1 and TIM-3 differentially regulate subsets of mouse IL-17A-producing γδ T cells.

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| S-EPMC9732671 | biostudies-literature

γδ T cells producing IL-17A regulate adipose Treg homeostasis and thermogenesis

Project description:RNA sequencing of PLZF+ and PLZF- γδ T cell subsets from adipose tissue for gene expression analysis

2018-05-10 | GSE103742 | GEO

Cancer cell-expressed BTNL2 facilitates tumour immune escape via engagement with IL-17A-producing γδ T cells.

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| S-EPMC8752682 | biostudies-literature

Double-negative T cells ameliorate psoriasis by selectively inhibiting IL-17A-producing γδ<sup>low</sup> T cells.

Project description:BackgroundPsoriasis is a chronic immune-mediated skin condition. Although biologic treatments are effective in controlling psoriasis, some patients do not respond or lose response to these therapies. Thus, new strategies for psoriasis treatment are still urgently needed. Double-negative T cells (DNT) play a significant immunoregulatory role in autoimmune diseases. In this study, we aimed to evaluate the protective effect of DNT in psoriasis and explore the underlying mechanism.MethodsWe conducted a single adoptive transfer of DNT into an imiquimod (IMQ)-induced psoriasis mouse model through tail vein injection. The skin inflammation and IL-17A producing γδ T cells were evaluated.ResultsDNT administration significantly reduced the inflammatory response in mouse skin, characterized by decreased skin folds, scales, and red patches. After DNT treatment, the secretion of IL-17A by RORc+ γδlow T cells in the skin was selectively suppressed, resulting in an amelioration of skin inflammation. Transcriptomic data suggested heightened expression of NKG2D ligands in γδlow T cells within the mouse model of psoriasis induced by IMQ. When blocking the NKG2D ligand and NKG2D (expressed by DNT) interaction, the cytotoxic efficacy of DNT against RORc+IL17A+ γδlow T cells was attenuated. Using Ccr5-/- DNT for treatment yielded evidence that DNT migrates into inflamed skin tissue and fails to protect IMQ-induced skin lesions.ConclusionsDNT could migrate to inflamed skin tissue through CCR5, selectively inhibit IL-17-producing γδlow T cells and finally ameliorate mouse psoriasis. Our study provides feasibility for using immune cell therapy for the prevention and treatment of psoriasis in the clinic.

| S-EPMC10988838 | biostudies-literature

IL-17A-producing resident memory γδ T cells orchestrate the innate immune response to secondary oral Listeria monocytogenes infection.

Project description:Memory γδ T cells are important for the clearance of Listeria monocytogenes infection in the intestinal mucosa. However, the mechanisms by which memory γδ T cells provide protection against secondary oral infection are poorly understood. Here we used a recombinant strain of L. monocytogenes that efficiently invades the intestinal epithelium to show that Vγ4(+) memory γδ T cells represent a resident memory (Trm) population in the mesenteric lymph nodes (MLNs). The γδ Trm exhibited a remarkably static pattern of migration that radically changed following secondary oral L. monocytogenes infection. The γδ Trms produced IL-17A early after rechallenge and formed organized clusters with myeloid cells surrounding L. monocytogenes replication foci only after a secondary oral infection. Antibody blocking studies showed that in addition to IL-17A, the chemokine receptor C-X-C chemokine receptor 3 (CXCR3) is also important to enable the local redistribution of γδ Trm cells and myeloid cells specifically near the sites of L. monocytogenes replication within the MLN to restrict bacterial growth and spread. Our findings support a role for γδ Trms in orchestrating protective immune responses against intestinal pathogens.

| S-EPMC4968747 | biostudies-literature

CD4+ and γδ T Cells are the main Producers of IL-22 and IL-17A in Lymphocytes from Mycobacterium bovis-infected Cattle.

Project description:Gene transcription studies have identified dual roles for the cytokines IL-17A and IL-22 in bovine tuberculosis, where they show potential as both predictors of vaccine success and correlates of infection. To allow for a detailed investigation of the cell populations responsible for production of these cytokines, we have utilised a novel bovine IL-22 specific recombinant antibody for flow cytometry. Bovine tuberculin (PPDB) induced greater IL-22 and IL-17A production in Mycobacterium bovis (M. bovis)-infected cattle compared to non-infected controls, while PWM-induced cytokine levels were similar between the two groups. In M. bovis-infected animals, PPDB specific IL-22 and IL-17A responses were observed in both CD4+ T cell and γδ T cell populations. Although both cytokines were detected in both cell types, IL-22/IL-17A double producers were rare and confined mainly to the γδ T cell population. These results support previous gene transcription studies and extend the observation of increased IL-22 and IL-17A responses in M. bovis-infected animals to the level of protein production. We were also able to characterise the cell populations responsible for these disease-related cytokine responses. The data generated can be used to further our understanding of the immunopathology of bovine tuberculosis and to produce more sensitive and specific immune-diagnostic reagents.

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IL-17A and IL-17F producing cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-11-20 | GSE189232 | GEO

Short-Term Exposure to a Western Diet Induces Psoriasiform Dermatitis by Promoting Accumulation of IL-17A-Producing γδ T Cells.

Project description:A Western diet (WD)-characterized by its high fat and simple sugar content-is thought to predispose individuals to inflammatory skin diseases such as psoriasis through the development of obesity. This scenario, however, is being challenged by emerging data suggesting that dietary components, rather than obesity itself, may exacerbate psoriasis. We herein show that short-term feeding with a diet analogous to the WD in mice leads to T helper type 1-/T helper type 17-biased skin inflammation before significant body weight gain. Feeding for as little as 4 weeks with a WD promoted mild dermatitis and accumulation of IL-17A-producing γδ T cells in the skin. Strikingly, γδ T cells from WD-fed mice exhibited enriched IL-23 receptor expression and increased the potential to produce IL-17A after IL-23 stimulation. In contrast to wild-type mice, WD-fed TCRδ-deficient and CCR6-deficient mice had reduced skin inflammation and IL-17A expression. Supplementation with a bile acid sequestrant, cholestyramine, prevented WD-induced skin inflammation along with a reduction in the infiltration of γδ T cells and the expression of proinflammatory mediators. In summary, our data revealed dietary influences in inflammatory signaling in the skin. The dysregulation of IL-23 pathways and bile acid pathways may be key to the development of WD-associated psoriasiform dermatitis.

| S-EPMC7537492 | biostudies-literature

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