{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T13:50:28Z","timestamp":1776779428296,"version":"3.51.2"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T00:00:00Z","timestamp":1712275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["#22K19446"],"award-info":[{"award-number":["#22K19446"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["#23H04789"],"award-info":[{"award-number":["#23H04789"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["22H02852"],"award-info":[{"award-number":["22H02852"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["#21H00439"],"award-info":[{"award-number":["#21H00439"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["#19K07488"],"award-info":[{"award-number":["#19K07488"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["19H05431"],"award-info":[{"award-number":["19H05431"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Autoimmune diseases often arise from conditions where the immune system is compromised. While lymphopenia-induced proliferation (LIP) is crucial for immune system development and maturation, it is also caused by environmental insults, such as infection, and becomes a risk factor for autoimmunity in adults. We used Dsg3H1 TCR transgenic mice, whose T cells are designed to recognize desmogrein-3, a skin antigen, to explore the impact of lymphopenia on post-thymic tolerance. Dsg3H1 mice are known to delete the most highly autoreactive T cells in the thymus, and develop only subtle immune-mediated pathology in the steady state. However, we found that transient lymphopenia induced by total body irradiation (TBI) or cyclophosphamide (CY) results in massive dermatitis in Dsg3H1 mice. The symptoms included expansion and development of self-reactive T cells, their differentiation into CD44high IL-17-producing helper T cells, and severe neutrophilic inflammation. Repopulation of FOXP3+ T regulatory cells after lymphopenia normally occurred, suggesting escape of skin-reactive conventional T cells from control by regulatory T cells. Furthermore, we found that a depletion of the intestinal microbiota by antibiotics prevents CY-induced dermatitis, indicating roles of the commensal intestinal microbiota in LIP and Th17 development in vivo. The current data suggested that post-thymic tolerance of Dsg3H1 mice is established on a fragile balance in the lymphoreplete immune environment and broken by the interplay between lymphopenia and intestinal microbiota. The dynamic phenotypes observed in Dsg3H1 mice prompt a re-evaluation of opportunistic lymphopenia together with the microbiota as pivotal environmental factors, impacting individuals with genetic predispositions for autoimmune diseases.<\/jats:p>","DOI":"10.1093\/intimm\/dxae018","type":"journal-article","created":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T00:08:19Z","timestamp":1712189299000},"page":"413-424","source":"Crossref","is-referenced-by-count":1,"title":["Disruption of post-thymic tolerance in skin-reactive TCR transgenic mice through the interaction of lymphopenia and intestinal microbiota"],"prefix":"10.1093","volume":"36","author":[{"given":"Hodaka","family":"Hayabuchi","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Keio University School of Medicine , 35 Shinanomachi, East Lecture Hall 4F, Shinjuku, Tokyo 160-8582 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukiko","family":"Tokifuji","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Keio University School of Medicine , 35 Shinanomachi, East Lecture Hall 4F, Shinjuku, Tokyo 160-8582 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hayato","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , 35 Shinanomachi, Shinjuku, Tokyo 160-8582 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Amagai","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Keio University School of Medicine , 35 Shinanomachi, Shinjuku, Tokyo 160-8582 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiko","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Keio University School of Medicine , 35 Shinanomachi, East Lecture Hall 4F, Shinjuku, Tokyo 160-8582 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shunsuke","family":"Chikuma","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Keio University School of Medicine , 35 Shinanomachi, East Lecture Hall 4F, Shinjuku, Tokyo 160-8582 , Japan"},{"name":"Institute of Biotechnology, College of Life Sciences and Medicine, National Tsing-Hua University , 101-2 Kuang-Fu Road, Hsinchu, 300044 , Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,4,5]]},"reference":[{"key":"2024071313363547100_CIT0001","first-page":"383","article-title":"Negative selection\u2014clearing out the bad apples from the T-cell repertoire","volume-title":"Nat Rev Immunol","author":"Palmer","year":"2003"},{"key":"2024071313363547100_CIT0002","first-page":"eabf3111","article-title":"Protection against autoimmunity is driven by thymic epithelial cell-mediated regulation of T(reg) development","volume-title":"Sci Immunol","author":"Haftmann","year":"2021"},{"key":"2024071313363547100_CIT0003","first-page":"68","article-title":"Disruption of a new forkhead\/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse","volume-title":"Nat Genet","author":"Brunkow","year":"2001"},{"key":"2024071313363547100_CIT0004","first-page":"18","article-title":"X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy","volume-title":"Nat Genet","author":"Wildin","year":"2001"},{"key":"2024071313363547100_CIT0005","first-page":"330","article-title":"Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells","volume-title":"Nat Immunol","author":"Fontenot","year":"2003"},{"key":"2024071313363547100_CIT0006","first-page":"337","article-title":"An essential role for Scurfin in CD4+ CD25+ T regulatory cells","volume-title":"Nat Immunol","author":"Khattri","year":"2003"},{"key":"2024071313363547100_CIT0007","first-page":"271","article-title":"CTLA-4 control over Foxp3+ regulatory T cell function","volume-title":"Science","author":"Wing","year":"2008"},{"key":"2024071313363547100_CIT0008","first-page":"1322","article-title":"An essential role for the IL-2 receptor in T(reg) cell function","volume-title":"Nat Immunol","author":"Chinen","year":"2016"},{"key":"2024071313363547100_CIT0009","first-page":"141","article-title":"Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor","volume-title":"Immunity","author":"Nishimura","year":"1999"},{"key":"2024071313363547100_CIT0010","first-page":"685","article-title":"PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector\/memory T cells","volume-title":"Science","author":"Hasegawa","year":"2004"},{"key":"2024071313363547100_CIT0011","first-page":"636618","article-title":"Influence of PTPN22 allotypes on innate and adaptive immune function in health and disease","volume-title":"Front Immunol","author":"Armitage","year":"2021"},{"key":"2024071313363547100_CIT0012","first-page":"1646","article-title":"Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child","volume-title":"Nat Med","author":"Ogishi","year":"2021"},{"key":"2024071313363547100_CIT0013","first-page":"482","article-title":"CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes","volume-title":"J Allergy Clin Immunol","author":"Caudy","year":"2007"},{"key":"2024071313363547100_CIT0014","first-page":"736","article-title":"Therapeutic options for CTLA-4 insufficiency","volume-title":"J Allergy Clin Immunol","author":"Egg","year":"2022"},{"key":"2024071313363547100_CIT0015","first-page":"131","article-title":"Neonates support lymphopenia-induced proliferation","volume-title":"Immunity","author":"Min","year":"2003"},{"key":"2024071313363547100_CIT0016","first-page":"8732","article-title":"IL-7 is critical for homeostatic proliferation and survival of naive T cells","volume-title":"Proc Natl Acad Sci USA","author":"Tan","year":"2001"},{"key":"2024071313363547100_CIT0017","first-page":"547","article-title":"Maintaining the norm: T-cell homeostasis","volume-title":"Nat Rev Immunol","author":"Jameson","year":"2002"},{"key":"2024071313363547100_CIT0018","first-page":"1784","article-title":"Lymphopenia-induced spontaneous T-cell proliferation as a cofactor for autoimmune disease development","volume-title":"Blood","author":"Le Campion","year":"2009"},{"key":"2024071313363547100_CIT0019","first-page":"565","article-title":"Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD\/SCID recipient mice","volume-title":"J Clin Invest","author":"Bending","year":"2009"},{"key":"2024071313363547100_CIT0020","first-page":"481","article-title":"Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice","volume-title":"Eur J Immunol","author":"Yasunami","year":"1988"},{"key":"2024071313363547100_CIT0021","first-page":"604","article-title":"Promotion of spontaneous diabetes in non-obese diabetes-prone mice by cyclophosphamide","volume-title":"Diabetologia","author":"Harada","year":"1984"},{"key":"2024071313363547100_CIT0022","first-page":"478","article-title":"Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells","volume-title":"Nat Immunol","author":"Sprent","year":"2011"},{"key":"2024071313363547100_CIT0023","first-page":"431","article-title":"Autoimmunity and immunological tolerance in autoimmune bullous diseases","volume-title":"Int Immunol","author":"Takahashi","year":"2019"},{"key":"2024071313363547100_CIT0024","first-page":"112","article-title":"T cell autoimmunity and immune regulation to desmoglein 3, a pemphigus autoantigen","volume-title":"J Dermatol","author":"Takahashi","year":"2023"},{"key":"2024071313363547100_CIT0025","first-page":"3677","article-title":"Desmoglein 3-specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice","volume-title":"J Clin Invest","author":"Takahashi","year":"2011"},{"key":"2024071313363547100_CIT0026","first-page":"e2026763118","article-title":"Peripheral tolerance by Treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus","volume-title":"Proc Natl Acad Sci USA","author":"Iriki","year":"2021"},{"key":"2024071313363547100_CIT0027","first-page":"3065","article-title":"Th17 cells carrying TCR recognizing epidermal autoantigen induce psoriasis-like skin inflammation","volume-title":"J Immunol","author":"Nishimoto","year":"2013"},{"key":"2024071313363547100_CIT0028","first-page":"108646","article-title":"Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition","volume-title":"iScience","author":"Tokifuji","year":"2024"},{"key":"2024071313363547100_CIT0029","first-page":"470","article-title":"Idiopathic CD4 T-cell lymphocytopenia: a case report of a young boy with recalcitrant warts","volume-title":"J Cutan Med Surg","author":"Cheung","year":"2016"},{"key":"2024071313363547100_CIT0030","first-page":"109","article-title":"Skin manifestations in AIDS patients","volume":"71","author":"Staughton","year":"1990","journal-title":"Br J Clin Pract Suppl"},{"key":"2024071313363547100_CIT0031","first-page":"186","article-title":"Psoriasis associated with idiopathic CD4+ T-cell lymphopenia: a regulatory T-cell defect","volume-title":"Br J Dermatol","author":"Baroudjian","year":"2014"},{"key":"2024071313363547100_CIT0032","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1046\/j.1365-2133.1997.01802.x","article-title":"Active psoriasis and profound CD4+ lymphocytopenia","volume":"136","author":"Hardman","year":"1997","journal-title":"Br J Dermatol"},{"key":"2024071313363547100_CIT0033","first-page":"470","article-title":"HIV-associated psoriasis: pathogenesis, clinical features, and management","volume-title":"Lancet Infect Dis","author":"Morar","year":"2010"},{"key":"2024071313363547100_CIT0034","first-page":"e39750","article-title":"Marking and quantifying IL-17A-producing cells in vivo","volume-title":"PLoS One","author":"Price","year":"2012"},{"key":"2024071313363547100_CIT0035","first-page":"222","article-title":"Auto-reconstitution of the T-cell compartment by radioresistant hematopoietic cells following lethal irradiation and bone marrow transplantation","volume-title":"Exp Hematol","author":"Bosco","year":"2010"},{"key":"2024071313363547100_CIT0036","first-page":"845","article-title":"Th17 and regulatory T cells in mediating and restraining inflammation","volume-title":"Cell","author":"Littman","year":"2010"},{"key":"2024071313363547100_CIT0037","first-page":"283","article-title":"The pathogenicity of Th17 cells in autoimmune diseases","volume-title":"Semin Immunopathol","author":"Yasuda","year":"2019"},{"key":"2024071313363547100_CIT0038","first-page":"8959","article-title":"Full restoration of peripheral Foxp3+ regulatory T cell pool by radioresistant host cells in scurfy bone marrow chimeras","volume-title":"Proc Natl Acad Sci USA","author":"Komatsu","year":"2007"},{"key":"2024071313363547100_CIT0039","first-page":"211ra157","article-title":"Aldehyde dehydrogenase expression drives human regulatory T cell resistance to post-transplantation cyclophosphamide","volume-title":"Sci Transl Med","author":"Kanakry","year":"2013"},{"key":"2024071313363547100_CIT0040","first-page":"971","article-title":"The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide","volume-title":"Science","author":"Viaud","year":"2013"},{"key":"2024071313363547100_CIT0041","first-page":"229","article-title":"Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis","volume-title":"Cell","author":"Rakoff-Nahoum","year":"2004"},{"key":"2024071313363547100_CIT0042","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.chom.2008.09.009","article-title":"Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine","volume":"4","author":"Ivanov","year":"2008","journal-title":"Cell Host Microbe"},{"key":"2024071313363547100_CIT0043","first-page":"485","article-title":"Induction of intestinal Th17 cells by segmented filamentous bacteria","volume-title":"Cell","author":"Ivanov","year":"2009"},{"key":"2024071313363547100_CIT0044","first-page":"1007","article-title":"Involvement of avidity for major histocompatibility complex in homeostasis of naive and memory T cells","volume-title":"J Exp Med","author":"Kassiotis","year":"2003"},{"key":"2024071313363547100_CIT0045","first-page":"40","article-title":"A role for TCR affinity in regulating naive T cell homeostasis","volume-title":"J Immunol","author":"Kieper","year":"2004"},{"key":"2024071313363547100_CIT0046","first-page":"46037","article-title":"Intestinal microbiota link lymphopenia to murine autoimmunity via PD-1(+)CXCR5(\u2212\/dim) B-helper T cell induction","volume-title":"Sci Rep","author":"Eri","year":"2017"},{"key":"2024071313363547100_CIT0047","first-page":"5788","article-title":"Homeostatic proliferation of naive CD4+ T cells in mesenteric lymph nodes generates gut-tropic Th17 cells","volume-title":"J Immunol","author":"Kawabe","year":"2013"},{"key":"2024071313363547100_CIT0048","first-page":"3158","article-title":"Recent immune status determines the source of antigens that drive homeostatic T cell expansion","volume-title":"J Immunol","author":"Kieper","year":"2005"},{"key":"2024071313363547100_CIT0049","first-page":"2391","article-title":"Commensal microflora and interferon-gamma promote steady-state interleukin-7 production in vivo","volume-title":"Eur J Immunol","author":"Shalapour","year":"2010"},{"key":"2024071313363547100_CIT0050","first-page":"e31939","article-title":"Interleukin-7 links T lymphocyte and intestinal epithelial cell homeostasis","volume-title":"PLoS One","author":"Shalapour","year":"2012"},{"key":"2024071313363547100_CIT0051","first-page":"149","article-title":"Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells","volume-title":"Nat Immunol","author":"Guimond","year":"2009"},{"key":"2024071313363547100_CIT0052","first-page":"367","article-title":"Th17 cell induction by adhesion of microbes to intestinal epithelial cells","volume-title":"Cell","author":"Atarashi","year":"2015"},{"key":"2024071313363547100_CIT0053","first-page":"2197","article-title":"Microbial translocation augments the function of adoptively transferred self\/tumor-specific CD8+ T cells via TLR4 signaling","volume-title":"J Clin Invest","author":"Paulos","year":"2007"},{"key":"2024071313363547100_CIT0054","first-page":"1321","article-title":"Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis","volume-title":"J Exp Med","author":"Feng","year":"2010"},{"key":"2024071313363547100_CIT0055","first-page":"5836","article-title":"Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23\/IL-17 axis","volume-title":"J Immunol","author":"van der Fits","year":"2009"},{"key":"2024071313363547100_CIT0056","first-page":"2577","article-title":"IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis","volume-title":"J Exp Med","author":"Chan","year":"2006"},{"key":"2024071313363547100_CIT0057","first-page":"78","article-title":"Dysbiosis of gut microbiota and its correlation with dysregulation of cytokines in psoriasis patients","volume-title":"BMC Microbiol","author":"Zhang","year":"2021"},{"key":"2024071313363547100_CIT0058","first-page":"1287","article-title":"Gut microbiota dysbiosis in a cohort of patients with psoriasis","volume-title":"Br J Dermatol","author":"Hidalgo-Cantabrana","year":"2019"},{"key":"2024071313363547100_CIT0059","first-page":"1114586","article-title":"Association of gut microbiome and metabolites with onset and treatment response of patients with pemphigus vulgaris","volume-title":"Front Immunol","author":"Wang","year":"2023"},{"key":"2024071313363547100_CIT0060","first-page":"111470","article-title":"Comparison of gut microbiota dysbiosis between pemphigus vulgaris and bullous pemphigoid","volume-title":"Int Immunopharmacol","author":"Han","year":"2024"},{"key":"2024071313363547100_CIT0061","first-page":"1792","article-title":"Lymphopenia in COVID-19: therapeutic opportunities","volume-title":"Cell Biol Int","author":"Fathi","year":"2020"},{"key":"2024071313363547100_CIT0062","first-page":"e04542","article-title":"New-onset guttate psoriasis secondary to COVID-19","volume-title":"Clin Case Rep","author":"Rouai","year":"2021"},{"key":"2024071313363547100_CIT0063","first-page":"1360","article-title":"New-onset pustular psoriasis in the setting of severe acute respiratory syndrome coronavirus 2 infection causing coronavirus disease 2019","volume-title":"JAAD Case Rep","author":"Mathieu","year":"2020"},{"key":"2024071313363547100_CIT0064","first-page":"527","article-title":"HLA-Cw*0602 and HIV-associated psoriasis","volume-title":"Br J Dermatol","author":"Mallon","year":"1998"}],"container-title":["International Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/intimm\/advance-article-pdf\/doi\/10.1093\/intimm\/dxae018\/57220900\/dxae018.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/36\/8\/413\/58535270\/dxae018.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/36\/8\/413\/58535270\/dxae018.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,13]],"date-time":"2024-07-13T14:01:18Z","timestamp":1720879278000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/intimm\/article\/36\/8\/413\/7641067"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,5]]},"references-count":64,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,4,5]]},"published-print":{"date-parts":[[2024,7,13]]}},"URL":"https:\/\/doi.org\/10.1093\/intimm\/dxae018","relation":{},"ISSN":["1460-2377"],"issn-type":[{"value":"1460-2377","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,8]]},"published":{"date-parts":[[2024,4,5]]}}}