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Here, using primary open-angle glaucoma as a model of chronic neurodegeneration, we demonstrate that dysregulated adaptive immunity is sufficient to promote retinal ganglion cell degeneration. Peripheral blood mononuclear cells from glaucoma patients, but not healthy donors, induced retinal ganglion cell loss following transfer into humanized immunodeficient mice without changes to the intraocular pressure, demonstrating a causal role for immune responses in the patient derived material. Comprehensive immune profiling further revealed selective changes in the regulatory T-cell compartment, indicating reduced activation, an impaired suppressive phenotype, and altered differentiation and trafficking states despite preserved overall regulatory T-cell abundance. We further demonstrate that transient expansion of regulatory T cells preserves visual function, reduced optic nerve axonal degeneration, and limited retinal ganglion cell loss in an experimental glaucoma model. Together, these findings identify failure of regulatory T-cell\u2013mediated immune tolerance as a mechanism that permits neurodegeneration in glaucoma and demonstrate that restoring immune regulation can ameliorate neuronal injury. Our data indicate that immune tolerance is a modifiable determinant of chronic neurodegeneration and suggest that immunoregulatory therapies may complement conventional pressure-lowering treatments to preserve vision in glaucoma.<\/jats:p>","DOI":"10.64898\/2026.09.17.26363354","type":"posted-content","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T21:45:11Z","timestamp":1789940711000},"source":"Crossref","is-referenced-by-count":0,"title":["Impaired regulatory T-cell\u2013mediated immune tolerance promotes neurodegeneration in glaucoma"],"prefix":"10.64898","author":[{"given":"Huilan","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The University of Iowa"},{"name":"Department of Ophthalmology, The First Affiliated Hospital, Hengyang Medical School, University of South China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merri-Grace","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The University of Iowa"},{"name":"Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City VA Health Care System"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeb R.","family":"Zacharias","sequence":"additional","affiliation":[{"name":"Human Immunology Core, The University of Iowa"},{"name":"Department of Microbiology and Immunology, The University of Iowa"},{"name":"Holden Comprehensive Cancer Center, University of Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin A.","family":"Boese","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The University of Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wallace L.M.","family":"Alward","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The University of Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young H.","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The University of Iowa"},{"name":"Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City VA Health Care System"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon C.D.","family":"Houtman","sequence":"additional","affiliation":[{"name":"Human Immunology Core, The University of Iowa"},{"name":"Department of Microbiology and Immunology, The University of Iowa"},{"name":"Holden Comprehensive Cancer Center, University of Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Linton","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The University of Iowa"},{"name":"Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City VA Health Care System"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy H.","family":"Kardon","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The University of Iowa"},{"name":"Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City VA Health Care System"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver W.","family":"Gramlich","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The University of Iowa"},{"name":"Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City VA Health Care System"},{"name":"Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3940-198X","authenticated-orcid":false,"given":"Markus H.","family":"Kuehn","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The University of Iowa"},{"name":"Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City VA Health Care System"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092309050656000_2026.09.17.26363354v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.08.001"},{"key":"2026092309050656000_2026.09.17.26363354v1.2","doi-asserted-by":"crossref","unstructured":"Zhao X , Zhang G , Wang Z , Zhang D , Xia Z , and Huo C . 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