Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis

Joosse, Maria E.; Charbit‐Henrion, Fabienne; Boisgard, Remy; Raatgeep, Rolien H C; Lindenbergh-Kortleve, Dicky J.; Costes, L M M; Nugteren, Sandrine; Guégan, Nicolas; Parlato, Marianna; Veenbergen, Sharon; Malan, Valérie; Nowak, Jan; Hollink, Iris H.I.M.; Escher, Johanna C.; Cerf‐Bensussan, Nadine; Samsom, Janneke N.

doi:10.1038/s41385-021-00423-5

Cited by 19 publications

(18 citation statements)

References 43 publications

(55 reference statements)

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“…These mutations may have differential effects on Treg cells versus effector T cells as CD25 deficiency results in defective IL-10 expression in CD4 + T cells (267) and lack of IL-10 expression by Treg cells in mice contributes to intestinal inflammation (46). Recently, a microduplication of the IL2RA locus associated with very-early-onset IBD which is attributed to increased IL-2 signaling (270). This increased IL-2 signaling potentiates the IFNg response after TCR activation (270,271).…”

Section: Monogenic Disorders Driven By Treg Cell Dysfunctionmentioning

confidence: 99%

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Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease

Jacobse

Rings

et al. 2021

Front. Immunol.

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FOXP3+ regulatory T cells (Treg cells) are a specialized population of CD4+ T cells that restrict immune activation and are essential to prevent systemic autoimmunity. In the intestine, the major function of Treg cells is to regulate inflammation as shown by a wide array of mechanistic studies in mice. While Treg cells originating from the thymus can home to the intestine, the majority of Treg cells residing in the intestine are induced from FOXP3neg conventional CD4+ T cells to elicit tolerogenic responses to microbiota and food antigens. This process largely takes place in the gut draining lymph nodes via interaction with antigen-presenting cells that convert circulating naïve T cells into Treg cells. Notably, dysregulation of Treg cells leads to a number of chronic inflammatory disorders, including inflammatory bowel disease. Thus, understanding intestinal Treg cell biology in settings of inflammation and homeostasis has the potential to improve therapeutic options for patients with inflammatory bowel disease. Here, the induction, maintenance, trafficking, and function of intestinal Treg cells is reviewed in the context of intestinal inflammation and inflammatory bowel disease. In this review we propose intestinal Treg cells do not compose fixed Treg cell subsets, but rather (like T helper cells), are plastic and can adopt different programs depending on microenvironmental cues.

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Section: Monogenic Disorders Driven By Treg Cell Dysfunctionmentioning

confidence: 99%

“…Recently, a microduplication of the IL2RA locus associated with very-early-onset IBD which is attributed to increased IL-2 signaling (270). This increased IL-2 signaling potentiates the IFNg response after TCR activation (270,271).…”

Section: Monogenic Disorders Driven By Treg Cell Dysfunctionmentioning

confidence: 99%

Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease

Jacobse

Rings

et al. 2021

Front. Immunol.

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“…IL-2, as a Th1-type cytokine, is critical for maintaining intestinal homeostasis. However, high expression of the IL-2 signaling pathway could predispose to colonic intestinal inflammation [ 46 ]. Our current results indicated that r Cs CP or Cs CA might down-regulate the inflammatory responses of colitis mice via elevating Treg cells in both the spleens and MLNs, inducing the release of Th2 cytokines (IL-10, IL-4 and IL-13), and restraining the production of IL-1β and IL-2 cytokines in serum.…”

Section: Discussionmentioning

confidence: 99%

Cysteine protease of Clonorchis sinensis alleviates DSS-induced colitis in mice

Xie

et al. 2022

PLoS Negl Trop Dis

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Background Currently, inflammatory bowel disease (IBD) has become a global chronic idiopathic disease with ever-rising morbidity and prevalence. Accumulating evidence supports the IBD-hygiene hypothesis that helminths and their derivatives have potential therapeutic value for IBD. Clonorchis sinensis (C. sinensis) mainly elicit Th2/Treg-dominated immune responses to maintain long-term parasitism in the host. This study aimed to evaluate the therapeutic effects of cysteine protease (CsCP) and adult crude antigen (CsCA) of C. sinensis, and C. sinensis (Cs) infection on DSS-induced colitis mice. Methods BALB/c mice were given 5% DSS daily for 7 days to induce colitis. During this period, mice were treated with rCsCP, CsCA or dexamethasone (DXM) every day, or Cs infection which was established in advance. Changes in body weight, disease activity index (DAI), colon lengths, macroscopic scores, histopathological findings, myeloperoxidase (MPO) activity levels, regulatory T cell (Treg) subset levels, colon gene expression levels, serum cytokine levels, and biochemical indexes were measured. Results Compared with Cs infection, rCsCP and CsCA alleviated the disease activity of acute colitis more significant without causing abnormal blood biochemical indexes. In comparison, rCsCP was superior to CsCA in attenuating colonic pathological symptoms, enhancing the proportion of Treg cells in spleens and mesenteric lymph nodes, and improving the secretion of inflammatory-related cytokines (e.g., IL-2, IL-4, IL-10 and IL-13) in serum. Combined with RNA-seq data, it was revealed that CsCA might up-regulate the genes related to C-type lectin receptor and intestinal mucosal repair related signal pathways (e.g., Cd209d, F13a1 and Cckbr) to reduce colon inflammation and benefit intestinal mucosal repair. Dissimilarly, rCsCP ameliorated colitis mainly through stimulating innate immunity, such as Toll like receptor (TLR) signaling pathway, down-regulating the expression of inflammatory cytokines (e.g., IL-12b, IL-23r and IL-7), thereby restraining the differentiation of Th1/Th17 cells. Conclusions Both rCsCP and CsCA showed good therapeutic effects on the treatment of acute colitis, but rCsCP is a better choice. rCsCP is a safe, effective, readily available and promising therapeutic agent against IBD mainly by activating innate immunity and regulating the IL-12/IL-23r axis.

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“…This is the case in human patients as well as in mouse models of SLE [ 39 , 74 ]. However, with regard to IBD, enhanced IL-2 signaling may predispose to disease manifestation as shown by a very early onset refractory colitis, in which a duplication of CD25 was found, which causes excessive STAT5 signaling [ 75 ]. Thus, IL-2 might be a double edged sword in the context of inflammation since it also boosts effector T cell proliferation.…”

Section: Therapies Affecting Tregs In Autoimmune Diseasesmentioning

confidence: 99%

Regulatory T cell function in autoimmune disease

Rajendeeran¹,

Tenbrock

2021

Journal of Translational Autoimmunity

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Autoimmune diseases are characterized by a failure of tolerance to own body components resulting in tissue damage. Regulatory T cells are gatekeepers of tolerance. This review focusses on the function and pathophysiology of regulatory T cells in the context of autoimmune diseases including rheumatoid and juvenile idiopathic arthritis as well as systemic lupus erythematosus with an overview over current and future therapeutic options to boost Treg function.

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Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis

Cited by 19 publications

References 43 publications

Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease

Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease

Cysteine protease of Clonorchis sinensis alleviates DSS-induced colitis in mice

Regulatory T cell function in autoimmune disease

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