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Cytokines and Intestinal Mucosal Immunity

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Front. Immunol. | doi: 10.3389/fimmu.2018.00362

Death receptor 3 signaling controls the balance between regulatory and effector lymphocytes in SAMP1/YitFc mice with Crohn’s disease-like ileitis

Zhaodong Li1, Ludovica F. Buttó1,  Kristine-Ann Buela2, Li-Guo Jia1,  Minh Lam1, John Ward1, Theresa Torres Pizarro2 and  Fabio Cominelli1*
  • 1Digestive Health Research Center, Case Western Reserve University, United States
  • 2Departments of Pathology, Case Western Reserve University, United States

Death receptor 3 (DR3), a member of the tumor necrosis factor receptor (TNFR) superfamily, has been implicated in regulating T helper type 1 (TH1), type 2 (TH2) and type 17 (TH17) responses as well as regulatory T cell (Treg) and innate lymphoid cell (ILC) functions during immune-mediated diseases. However, the role of DR3 in controlling lymphocyte functions in inflammatory bowel disease (IBD) is not fully understood. Recent studies have shown that activation of DR3 signaling modulates Treg expansion suggesting that stimulation of DR3 represent a potential therapeutic target in human inflammatory diseases, including Crohn’s disease (CD). In this study, we tested a specific DR3 agonistic antibody (4C12) in SAMP1/YitFc (SAMP) mice with CD-like-ileitis. Interestingly, treatment with 4C12 prior to disease manifestation markedly worsened the severity of ileitis in SAMP mice despite an increase in FoxP3+ lymphocytes in mesenteric lymph node (MLN) and small intestinal lamina propria (LP) cells. Disease exacerbation was dominated by overproduction of both TH1- and TH2-type cytokines and associated with expansion of dysfunctional CD25-FoxP3+ and ILC group 1 (ILC1) cells. These effects were accompanied by a reduction in CD25+FoxP3+ and ILC group 3 (ILC3) cells. By comparison, genetic deletion of DR3 effectively reversed the inflammatory phenotype in SAMP mice by promoting the expansion of CD25+FoxP3+ over CD25-FoxP3+ cells and the production of IL-10 protein. Collectively, our data demonstrate that DR3 signaling modulates a multicellular network, encompassing Tregs, T effectors and ILCs, governing disease development and progression in SAMP mice with CD-like ileitis. Manipulating DR3 signaling towards the restoration of the balance between protective and inflammatory lymphocytes may represent a novel and targeted therapeutic modality for patients with CD.

Keywords: Crohn’s Disease, IBD, Death receptor 3, SAMP1/YitFc, Ileitis, FOXP3+ regulatory T cells, FoxP3+CD25- cells, CD25- Tregs, intestinal inflammation, chronic inflammation, ILC, DR3, TL1A, regulatory T cells (T-Regs), Cd, Innate lymphoid cells (ILC)

Received: 14 Nov 2017; Accepted: 08 Feb 2018.

Edited by:

Carlo Selmi, Università degli Studi di Milano, Italy

Reviewed by:

Oberdan Leo, Université libre de Bruxelles, Belgium
Silvia Piconese, Sapienza Università di Roma, Italy  

Copyright: © 2018 Li, Buttó, Buela, Jia, Lam, Ward, Torres Pizarro and Cominelli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Fabio Cominelli, Case Western Reserve University, Digestive Health Research Center, 2109 Adelbert Road, Cleveland, 44106, OH, United States,