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The cornea is immune privileged, and anterior chamber-associated immune deviation (ACAID) governs its inner surface. However, the mechanisms that apply to corneal epithelial (outer surface) antigens remain unknown. Using an inducible, cornea-restricted neoantigen mouse model, we found that the cornea relies on inducible regulatory T cells (Tregs) rather than ignorance or ACAID for its epithelial antigens. Although the cornea is both avascular and alymphatic, its epithelial antigens are still efficiently presented by ocular surface-derived antigen-presenting cells to T cells in draining lymph nodes under homeostatic conditions, leading to conventional antigen-specific Treg expansion without ocular pathology. This tolerance was not absolute: systemic immunization redirected antigen-specific responses toward pathogenic effector T cells that disrupted epithelial barrier function. These findings identify Treg induction as a dominant mechanism of corneal epithelial immune homeostasis and demonstrate that inflammatory priming can render a tolerated corneal antigen into an autoimmune target, providing mechanistic insight into dry eye pathogenesis.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>This study shows that immune tolerance to corneal epithelial neoantigens relies not on immune privilege but on peripherally induced regulatory T cells in the draining lymph nodes that can be subverted by innate activation, shedding light on ocular surface disease pathophysiology.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.14.718505","type":"posted-content","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T17:35:16Z","timestamp":1776447316000},"source":"Crossref","is-referenced-by-count":0,"title":["Mechanisms of CD4+ T tolerance to a corneal epithelial neoantigen"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5118-2540","authenticated-orcid":false,"given":"Jeremias G.","family":"Galletti","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Baylor College of Medicine, Houston, TX"},{"name":"Institute of Experimental Medicine, Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7556-8950","authenticated-orcid":false,"given":"Kaitlin K.","family":"Scholand","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Baylor College of Medicine, Houston, TX"},{"name":"Department of Biosciences, Rice University, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3782-4383","authenticated-orcid":false,"given":"Jianming","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2584-9401","authenticated-orcid":false,"given":"Prashant","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7904-7075","authenticated-orcid":false,"given":"Elizaveta A.","family":"Demianova","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3053-751X","authenticated-orcid":false,"given":"Elle Joy J","family":"San Juan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1628-2893","authenticated-orcid":false,"given":"Laura","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9057-5494","authenticated-orcid":false,"given":"Cintia S.","family":"de Paiva","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Baylor College of Medicine, Houston, TX"},{"name":"Department of Biosciences, Rice University, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026042105050699000_2026.04.14.718505v1.1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1167\/iovs.65.5.21","article-title":"Age-Related Differences in the Mouse Corneal Epithelial Transcriptome and Their Impact on Corneal Wound Healing","volume":"65","year":"2024","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2026042105050699000_2026.04.14.718505v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-4182(04)80071-1"},{"key":"2026042105050699000_2026.04.14.718505v1.3","first-page":"1362336","article-title":"Single cell analysis of short-term dry eye induced changes in cornea immune cell populations","volume":"11","year":"2024","journal-title":"Front Med (Lausanne)"},{"key":"2026042105050699000_2026.04.14.718505v1.4","first-page":"692","article-title":"Flow-cytometric analysis of rare antigen-specific T cells","volume":"83","year":"2013","journal-title":"Cytometry. 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