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Mice Intestinal Inflammation in Gimap5-Deficient Flora-Dependent

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Mice Intestinal Inflammation in Gimap5-Deficient Flora-Dependent Loss of T Cell and B Cell Quiescence Precedes the Onset of Microbial Flora-Dependent Wasting Disease and Intestinal Inflammation in Gimap5-Deficient This information is current as Mice of October 2, 2021. Michael J. Barnes, Halil Aksoylar, Philippe Krebs, Tristan Bourdeau, Carrie N. Arnold, Yu Xia, Kevin Khovananth, Isaac Engel, Sosathya Sovath, Kristin Lampe, Eleana Laws, Amy Saunders, Geoffrey W. Butcher, Mitchell Kronenberg, Kris Steinbrecher, David Hildeman, H. Leighton Grimes, Downloaded from Bruce Beutler and Kasper Hoebe J Immunol 2010; 184:3743-3754; Prepublished online 26 February 2010; doi: 10.4049/jimmunol.0903164 http://www.jimmunol.org/content/184/7/3743 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2010/03/01/jimmunol.090316 Material 4.DC1 References This article cites 58 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/184/7/3743.full#ref-list-1 by guest on October 2, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Loss of T Cell and B Cell Quiescence Precedes the Onset of Microbial Flora-Dependent Wasting Disease and Intestinal Inflammation in Gimap5-Deficient Mice Michael J. Barnes,*,1 Halil Aksoylar,†,1 Philippe Krebs,* Tristan Bourdeau,† Carrie N. Arnold,* Yu Xia,* Kevin Khovananth,* Isaac Engel,‡ Sosathya Sovath,* Kristin Lampe,† Eleana Laws,† Amy Saunders,x Geoffrey W. Butcher,x Mitchell Kronenberg,‡ Kris Steinbrecher,† David Hildeman,† H. Leighton Grimes,† Bruce Beutler,* and Kasper Hoebe† Homeostatic control of the immune system involves mechanisms that ensure the self-tolerance, survival and quiescence of hema- topoietic-derived cells. In this study, we demonstrate that the GTPase of immunity associated protein (Gimap)5 regulates these Downloaded from processes in lymphocytes and hematopoietic progenitor cells. As a consequence of a recessive N-ethyl-N-nitrosourea–induced germline mutation in the P-loop of Gimap5, lymphopenia, hepatic extramedullary hematopoiesis, weight loss, and intestinal in- flammation occur in homozygous mutant mice. Irradiated fetal liver chimeric mice reconstituted with Gimap5-deficient cells lose weight and become lymphopenic, demonstrating a hematopoietic cell-intrinsic function for Gimap5. Although Gimap5-deficient CD4+ T cells and B cells appear to undergo normal development, they fail to proliferate upon Ag-receptor stimulation although NF- kB, MAP kinase and Akt activation occur normally. In addition, in Gimap5-deficient mice, CD4+ T cells adopt a CD44highCD62Llow http://www.jimmunol.org/ CD69low phenotype and show reduced IL-7ra expression, and T-dependent and T-independent B cell responses are abrogated. Thus, Gimap5-deficiency affects a noncanonical signaling pathway required for Ag-receptor–induced proliferation and lymphocyte quiescence. Antibiotic-treatment or the adoptive transfer of Rag-sufficient splenocytes ameliorates intestinal inflammation and weight loss, suggesting that immune responses triggered by microbial flora causes the morbidity in Gimap5-deficient mice. These data establish Gimap5 as a key regulator of hematopoietic integrity and lymphocyte homeostasis. The Journal of Immunology, 2010, 184: 3743–3754. any layers of regulation ensure homeostatic control of occur normally, the many diverse lineages of hematopoietic cells by guest on October 2, 2021 the immune system during development and throughout are continually generated in the bone marrow and thymus. Given M life. In fetal and neonatal mice, hematopoietic stem cells their potential to undergo clonal expansion and long-term survival, (HSCs) and precursor cells migrate from the fetal liver to the bone additional checkpoints are needed to limit the survival of self- marrow and thymus (1). Thereafter, maintenance of the HSC niche reactive T cells and B cells (3). In T cells, these checkpoints include involves both cell-extrinsic and cell-intrinsic mechanisms in which the induction of apoptosis in thymocytes that recognize self-Ags responsiveness to growth factors, cell cycle control, and breakdown with high affinity (negative selection) (4) and the mitigation of of metabolic by-products are essential (2). When these processes inappropriate immune responses by regulatory T cells (5). The availability of common–g-chain cytokines governs the size and composition of the T cell niche (6–8). Notably, IL-2, IL-7, and ‡ *Department of Genetics, Scripps Research Institute, La Jolla; La Jolla Institute for IL-15 promote T cell survival by modulating the expression of Allergy and Immunology, San Diego, CA 92037; †Cincinnati Children’sHospital Research Foundation, Cincinnati, OH 45229; and xThe Babraham Institute, Babraham Research Bcl-2–family member proteins. Campus,Cambridge,UnitedKingdom Somewhat paradoxically, mutations or conditions that partially 1M.J.B. and H.A. contributed equally to this article. impair T cell survival can be associated with the development of Received for publication September 29, 2009. Accepted for publication January 19, immunopathologies (9). One potential explanation for this associ- 2010. ation is that excess common–g-chain cytokines available in lym- This work was supported by National Institutes of Health/National Cancer Institute phopenic conditions allow the survival and proliferation of self- Grant 1R21CA133649-01, Public Health Service Grant P30 DK078392, NIH 5P01 reactive T cell clones. For example, when naive CD4+ T cells are AI070167, and R37 AI71922, and Competitive Strategic Grant and Ph.D. studentship funding from the U.K. Biotechnology and Biological Sciences Research Council (to transferred into Rag-deficient recipient mice, they undergo lym- G.W.B. and A.S.). phopenia-induced proliferation (LIP) and adopt a characteristic Address correspondence and reprint requests to Kasper Hoebe, Cincinnati Children’s phenotype similar to memory CD4+ T cells that includes the ex- Hospital Research Foundation, MLC7021, Room S5.421, 3333 Burnet Avenue, Cin- pression of increased amounts of CD44 (CD44high) and reduced cinnati, OH 45229. E-mail address: [email protected] amounts of CD62L (CD62Llow), whereas CD69 expression remains The online version of this article contains supplemental material. mostly unaffected (CD69low) (8, 10). In some genetic backgrounds, Abbreviations used in this paper: CLP, common lymphoid progenitor; ED, embryonic day; ENU, N-ethyl-N-nitrosourea; Gimap, GTPase of immunity associated protein; intestinal microbial florae promote the expansion of colitogenic + GMP, granulocyte/macrophage progenitor; HSC, hematopoietic stem cell; iNKT, in- IFN-g–producing CD4 T cells undergoing LIP, resulting in in- variant NKT; LIP, lymphopenia-induced proliferation; MEP, megakaryocyte-ery- testinal inflammation (11). Congenitally lymphopenic Tcra2/2 throid progenitor; PI, propidium iodide; TSRI, The Scripps Research Institute. mice also develop intestinal inflammation owing to excessive IL-4– Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 dependent Th2 cell and gd T cell responses (12–14). Lymphopenia www.jimmunol.org/cgi/doi/10.4049/jimmunol.0903164 3744 GIMAP5 MAINTAINS LYMPHOCYTE QUIESCENCE has also been linked to the precipitation of diabetes in animal aGal-Cer–mouse CD1d tetramers labeled with PE or APC were generated models (15, 16). Increased rates of T cell turnover, altered ratios of as described previously (34), and all Abs used for flow cytometry were pur- regulatory to conventional T cells, and acquisition of effector chasedfrom eBioscience (SanDiego, CA) or BioLegend (SanDiego, CA).Abs for immunoblotting were purchased from Cell Signaling Technology (Beverly, function by T cells undergoing LIP are all aspects of the lympho- MA). Purified CD3ε (145-2C11) and CD28 (37.51) abs (eBioscience) were penic environment that might favor the onset of immunopathology. used for T cell activation. F(ab9)2–anti-IgM (Jackson ImmunoResearch), anti- Homozygosity for the lyp mutation causes severe T cell lym- CD40 (eBioscience), rIL-4 (R&D Systems, Minneapolis, MN), LPS (Axxora, phopenia and has been shown to predispose rats to the development San Diego, CA) and PMA/ionomycin (Sigma-Aldrich, St. Louis, MO) were used for B cell activation. T cells and B cells were labeled with CFSE by in- of autoimmune diabetes (16) and intestinal inflammation (17). cubating MACS (Miltenyi Biotech, Auburn, CA) purified CD4+ Tcellsor However, lymphopenia caused by the lyp mutation alone is in- splenic B cells in 5 mM CFSE in PBS with 0.1% FCS for 10 min. ELISAs were sufficient to trigger immunopathology, which requires the presence used to measure serum cytokine concentrations (eBioscience). of additional modifier alleles at other loci in the genome (17–21). In In vivo cytotoxicity
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