KLRG1 impairs regulatory T‐cell competitive fitness in the gut

Meinicke, Holger; Bremser, Anna; Brack, Maria; Schrenk, Klaudia; Pircher, Hanspeter; Ízcue, Ana

doi:10.1111/imm.12749

Cited by 19 publications

(13 citation statements)

References 26 publications

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“…Our results are in concordance with observations in other models, where the lack of KLRG1 expression on T-cells conferred them a functional competitive advantage, because the KLRG1 ligation decreases the TCR signalling, inhibiting the proliferative capacity and decreasing cytokine production. 21 22 We hypothesised that the high production of cytokines, like IL-6 and IFN-γ, and proliferative ability of CD4+T cells in ILA subjects might be independent of their differentiation status (naïve vs memory). However, probably it is a result of the lack of KLRG1 expression, which is a ‘brake-molecule’.…”

Section: Discussionmentioning

confidence: 99%

CD4+T cells in ageing-associated interstitial lung abnormalities show evidence of pro-inflammatory phenotypic and functional profile

Machahua

Buendía-Roldán

Ocaña-Guzmán

et al. 2020

Thorax

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BackgroundInterstitial lung abnormalities (ILA) occur in around 10% of subjects over 60 years, and are associated with a higher rate of all-cause mortality. The pathogenic mechanisms are unclear, and the putative contribution of alterations in the immune response has not been explored. Normal ageing is associated with immune deficiencies, including Naïve T-cell decrease and greater expression of the proliferative-limiting, co-inhibitory receptor killer-cell lectin-like receptor G1 (KLRG1).ObjectiveTo evaluate the frequency and activation state of different T-cell subpopulations in ILA subjects.MethodsPeripheral blood mononuclear cells were obtained from 15 individuals with ILA, 21 age-matched controls and 28 healthy young subjects. T-cells phenotype was characterised by flow cytometry, and proliferation and activation by stimulation with anti-CD3/anti-CD28 or phorbol myristate acetate/ionomycin; KLRG1 isoforms were evaluated by western blot and cytokines were quantified by ELISA and Multiplex.ResultsA significant increase of Naïve CD4+T cells together with a decrease of central and effector memory CD4+T cells was observed in ILA compared with age-matched controls. CD4+T cells from ILA subjects exhibited greater basal proliferation, which raised after anti-CD3/anti-CD28 stimulation. Additionally, a significant increase in the levels of interleukin-6 and interferon gamma was observed in isolated CD4+T cells and plasma of ILA subjects. They also displayed fewer KLRG1+/CD4+T cells with an increase of circulating E-cadherin, the ligand of KLRG1+. No changes were observed with CD8+T cell subsets.ConclusionCD4+T cells from ILA subjects are highly proliferative and show an excessive functional activity, likely related to the loss of KLRG1 expression, which may contribute to an inflammatory state and the development of ILA.

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Section: Discussionmentioning

confidence: 99%

CD4+T cells in ageing-associated interstitial lung abnormalities show evidence of pro-inflammatory phenotypic and functional profile

Machahua

Buendía-Roldán

Ocaña-Guzmán

et al. 2020

Thorax

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“…ILT3 was described to inhibit the suppressive activity of Tregs (25). The expression of the inhibitory receptor KLRG1 was slightly increased on intestinal Tregs of DDC mice as compared with controls and has been recently shown to inhibit Treg competitive fitness in the gut (36). High expression of KLRG1 on Tregs was also shown to have a negative impact on proliferation as well as stability of Foxp3 expression, and KLRG1 + Tregs were more prone to apoptosis than KLRG1 2 Treg subsets in a NOD mouse model of type 1 diabetes (37).…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cells Control Regulatory T Cell Function Required for Maintenance of Intestinal Tissue Homeostasis

Hilpert

Sitte

Arnold

et al. 2019

The Journal of Immunology

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Dendritic cells (DCs) together with regulatory T cells (Tregs) are essential mediators of immune homeostasis. Disruption of function or frequency of either cell type can lead to fatal autoimmunity. We previously described that mice constitutively lacking DCs (ΔDC) develop autoimmunity characterized by reduced body weight, autoantibodies, and pronounced intestinal inflammation. In this study, we show that lack of DCs leads to an altered gene expression profile in peripheral but not thymic Tregs with increased expression of inhibitory receptors. The suppressive function of Tregs from DDC mice was impaired in T cell cocultures. In a model of transfer colitis, Tregs from ΔDC mice were only functional in the presence of DCs in recipient mice. Lack of MHC class II on DCs also resulted in upregulation of inhibitory receptors on Tregs, reduced body weight, and elevated serum IgA levels. Further analysis of the IgA response revealed an expansion of IgA + germinal center B cells and plasma cells in mesenteric lymph nodes and more IgA-coated commensal bacteria in feces of ΔDC mice. Thus, we show a critical role for DCs to establish intestinal homeostasis by regulating Treg function for prevention of spontaneous inflammation.

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“…KLRG1 is an inhibitory receptor expressed by Tregs, but in contrast to the inhibitory receptor CTLA-4, not every Treg has expression, and its expression is only found in a subset of effector-like Tregs. Studies have shown that Tregs lacking in KLRG1 have the advantage of accumulating in the colon but not in the lymphoid organs, indicating that KLRG1 restricts the accumulation of intestinal Tregs, and KLRG1 plays an inherent role in colonic Treg homeostasis, but it does not change the total number of Tregs [46].…”

Section: Regulatory Molecules Of Colonic Treg Production Andmentioning

confidence: 99%

The Generation and Regulation of Tissue-Resident Tregs and Their Role in Autoimmune Diseases

Wang

Zou

Zhang

et al. 2020

Journal of Immunology Research

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Regulatory T cells (Tregs), as an important subset of T cells, play an important role in maintaining body homeostasis by regulating immune responses and preventing autoimmune diseases. In-depth research finds that Tregs have strong instability and plasticity, and according to their developmental origin, Tregs can be classified into thymic-derived Tregs (tTregs), endogenous-induced Tregs (pTregs), which are produced by antigen-stimulated T cells in the periphery in vivo, and induced Tregs (iTregs), which differentiate from naïve T cells in vitro. In recent years, studies have found that Tregs are divided into lymphatic and tissue-resident Tregs according to their location. Research on the generation and function of lymphoid Tregs has been more comprehensive and thorough, but the role of tissue Tregs is still in the exploratory stage, and it has become a research hot spot. In this review, we discuss the instability and plasticity of Tregs and the latest developments of tissue-resident Tregs in the field of biology, including adipose tissue, colon, skeletal muscle, and other Tregs that have been recently discovered as well as their production, regulation, and function in specific tissues and their role in the pathogenesis of autoimmune diseases.

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KLRG1 impairs regulatory T‐cell competitive fitness in the gut

Cited by 19 publications

References 26 publications

CD4+T cells in ageing-associated interstitial lung abnormalities show evidence of pro-inflammatory phenotypic and functional profile

CD4+T cells in ageing-associated interstitial lung abnormalities show evidence of pro-inflammatory phenotypic and functional profile

Dendritic Cells Control Regulatory T Cell Function Required for Maintenance of Intestinal Tissue Homeostasis

The Generation and Regulation of Tissue-Resident Tregs and Their Role in Autoimmune Diseases

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