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Lymphopenia or reduced lymphocyte number is implicated in autoimmune diseases, yet little is known about the homeostatic mechanisms. Here, it is reported that the replication protein A1 (RPA1) plays a critical role in T cell homeostasis. Utilizing T cell\u2010specific <jats:italic>Rpa1<\/jats:italic>\u2010deficient (<jats:italic>Rpa1<jats:sup>fl\/fl<\/jats:sup> Cd4\u2010cre<\/jats:italic>) mice, loss of <jats:italic>Rpa1<\/jats:italic> results in lymphopenia through restraining peripheral T cell population and limiting TCR repertoire diversity. Moreover, <jats:italic>Rpa1<jats:sup>fl\/fl<\/jats:sup> Cd4\u2010cre<\/jats:italic> mice exhibit increased susceptibility to inflammatory diseases, including colitis and hepatitis. Clinical analysis reveals that the expression of RPA1 is reduced in patients with ulcerative colitis or other autoinflammatory diseases. Mechanistically, depletion of RPA1 activates ZBP1\u2010RIPK3 signaling through triggering the genomic DNA leakage into cytosol, consequently resulting in T cell necroptosis. This necroptotic T cell death induced by RPA1 deficiency allows the release of damage\u2010associated molecular patterns (DAMPs), which in turn recruits leukocytes and exacerbates inflammatory response. Reciprocally, chemical or genetic inhibition of necroptosis signaling can ameliorate the <jats:italic>Rpa1<\/jats:italic> deficiency\u2010induced inflammatory damage. The studies thus uncover the importance of RPA1\u2010ZBP1\u2010RIPK3 axis in T cell homeostasis and provide a promising strategy for autoinflammatory disease treatment.<\/jats:p>","DOI":"10.1002\/advs.202206344","type":"journal-article","created":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T23:17:56Z","timestamp":1675207076000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Loss of RPA1 Impairs Peripheral T Cell Homeostasis and Exacerbates Inflammatory Damage through Triggering T Cell Necroptosis"],"prefix":"10.1002","volume":"10","author":[{"given":"Jia","family":"Song","sequence":"first","affiliation":[{"name":"Department of Geriatric Dentistry Department of Dental Materials &amp; Dental Medical Devices Testing Center National Engineering Research Center of Oral Biomaterials and Digital Medical Devices NMPA Key Laboratory for Dental Materials Beijing Laboratory of Biomedical Materials &amp; Beijing Key Laboratory of Digital Stomatology Peking University School and Hospital of Stomatology  Beijing 100081 P. 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