Dataset Information

Genetic models reveal origin, persistence and non-redundant functions of IL-17-producing ?? T cells.

ABSTRACT: ?? T cells are highly conserved in jawed vertebrates, suggesting an essential role in the immune system. However, ?? T cell-deficient Tcrd ^-/- mice display surprisingly mild phenotypes. We hypothesized that the lack of ?? T cells in constitutive Tcrd ^-/- mice is functionally compensated by other lymphocytes taking over genuine ?? T cell functions. To test this, we generated a knock-in model for diphtheria toxin-mediated conditional ?? T cell depletion. In contrast to IFN-?-producing ?? T cells, IL-17-producing ?? T cells (T??17 cells) recovered inefficiently after depletion, and their niches were filled by expanding Th17 cells and ILC3s. Complementary genetic fate mapping further demonstrated that T??17 cells are long-lived and persisting lymphocytes. Investigating the function of ?? T cells, conditional depletion but not constitutive deficiency protected from imiquimod-induced psoriasis. Together, we clarify that fetal thymus-derived T??17 cells are nonredundant local effector cells in IL-17-driven skin pathology.

SUBMITTER: Sandrock I

PROVIDER: S-EPMC6279411 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic models reveal origin, persistence and non-redundant functions of IL-17-producing γδ T cells.

Sandrock Inga I Reinhardt Annika A Ravens Sarina S Binz Christoph C Wilharm Anneke A Martins Joana J Oberdörfer Linda L Tan Likai L Lienenklaus Stefan S Zhang Baojun B Naumann Ronald R Zhuang Yuan Y Krueger Andreas A Förster Reinhold R Prinz Immo I

The Journal of experimental medicine 20181119 12

γδ T cells are highly conserved in jawed vertebrates, suggesting an essential role in the immune system. However, γδ T cell-deficient Tcrd -/- mice display surprisingly mild phenotypes. We hypothesized that the lack of γδ T cells in constitutive Tcrd -/- mice is functionally compensated by other lymphocytes taking over genuine γδ T cell functions. To test this, we generated a knock-in model for diphtheria toxin-mediated conditional γδ T cell depletion. In cont ...[more]

PMID: 30455268

Similar Datasets

Project description:In HIV/SIV-infected humans and rhesus macaques (RMs), a severe depletion of intestinal CD4(+) T-cells producing interleukin IL-17 and IL-22 associates with loss of mucosal integrity and chronic immune activation. However, little is known about the function of IL-17 and IL-22 producing cells during lentiviral infections. Here, we longitudinally determined the levels and functions of IL-17, IL-22 and IL-17/IL-22 producing CD4(+) T-cells in blood, lymph node and colorectum of SIV-infected RMs, as well as how they recover during effective ART and are affected by ART interruption. Intestinal IL-17 and IL-22 producing CD4(+) T-cells are polyfunctional in SIV-uninfected RMs, with the large majority of cells producing four or five cytokines. SIV infection induced a severe dysfunction of colorectal IL-17, IL-22 and IL-17/IL-22 producing CD4(+) T-cells, the extent of which associated with the levels of immune activation (HLA-DR(+)CD38(+)), proliferation (Ki-67+) and CD4(+) T-cell counts before and during ART. Additionally, Th17 cell function during ART negatively correlated with residual plasma viremia and levels of sCD163, a soluble marker of inflammation and disease progression. Furthermore, IL-17 and IL-22 producing cell frequency and function at various pre, on, and off-ART experimental points associated with and predicted total SIV-DNA content in the colorectum and blood. While ART restored Th22 cell function to levels similar to pre-infection, it did not fully restore Th17 cell function, and all cell types were rapidly and severely affected--both quantitatively and qualitatively--after ART interruption. In conclusion, intestinal IL-17 producing cell function is severely impaired by SIV infection, not fully normalized despite effective ART, and strongly associates with inflammation as well as SIV persistence off and on ART. As such, strategies able to preserve and/or regenerate the functions of these CD4(+) T-cells central for mucosal immunity are critically needed in future HIV cure research.

Project description:Interleukin-1 (IL-1) is a major "alarm" upstream pro-inflammatory cytokine that also affects immunity and hematopoiesis by inducing cytokine cascades. In the tumor arena, IL-1 is produced by malignant or microenvironmental cells. As a pleiotropic cytokine, IL-1 is involved in tumorigenesis and tumor invasiveness but also in the control of anti-tumor immunity. IL-1? and IL-1? are the major agonists of IL-1, while IL-1Ra is a physiological inhibitor of pre-formed IL-1. In their secreted form, IL-1? and IL-1? bind to the same receptors and induce the same biological functions, but IL-1? and IL-1? differ in their compartmentalization within the producing cell or the microenvironment. IL-1? is only active in its processed, secreted form, and mediates inflammation, which promotes carcinogenesis, tumor invasiveness, and immunosuppression, whereas IL-1? is mainly cell-associated and in the tumor context, when expressed on the cell membrane, it stimulates anti-tumor cell immunity manifested by tumor regression. In the tumor milieu, extracellular levels of IL-1? are usually low and do not stimulate broad inflammation that promotes progression. Immunosuppression induced by IL-1? in the tumor microenvironment, mainly through MDSC induction, usually inhibits or masks anti-tumor cell immunity induced by cell-associated IL-1?. However, in different tumor systems, redundant or unique patterns of IL-1? and IL-1? expression and function have been observed. Recent breakthroughs in inflammasome biology and IL-1? processing/secretion have spurred the development of novel anti-IL-1 agents, which are being used in clinical trials in patients with diverse inflammatory diseases. Better understanding of the integrative role of IL-1? and IL-1? in distinct malignancies will facilitate the application of novel IL-1 modulation approaches at the bedside, in cancer patients with minimal residual disease (MRD), as an adjunct to conventional approaches to reduce the tumor burden.

Dataset Information

Genetic models reveal origin, persistence and non-redundant functions of IL-17-producing ?? T cells.

Publications

Genetic models reveal origin, persistence and non-redundant functions of IL-17-producing γδ T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets