{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T22:00:52Z","timestamp":1792101652422,"version":"4.4.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>Glaucoma, a leading cause of irreversible blindness, involves complex mechanisms beyond elevated intraocular pressure (IOP), including immune signaling dysregulation. This study focused on the role of the T-cell receptor (TCR) signaling pathway, particularly the CD3\u03b6 chain, in retinal ganglion cell (RGC) degeneration and explored its potential as a neuroprotective target via immune modulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A mouse optic nerve crush model was used to mimic glaucomatous neurodegeneration. CD3\u03b6 knockdown was achieved using adeno-associated virus serotype 9 encoding short hairpin RNA. Retinal tissues were evaluated via immunofluorescence, Western blotting, and RT-qPCR to analyze the survival and death of RGCs and activation of key signaling pathways, including the MAPK and NF-\u03baB pathways. Changes in inflammatory cytokine profiles were assessed to examine the broader impact of TCR modulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CD3\u03b6 knockdown significantly improved RGC survival by reducing apoptosis and necroptosis. The neuroprotective effect of CD3\u03b6 knockdown was accompanied by the restoration of MAPK signaling, specifically the phosphorylation of ERK and p38, and attenuation of NF-\u03baB activation, indicated by decreased p65 phosphorylation. Furthermore, CD3\u03b6 knockdown reduced the levels of proinflammatory mediators (IL-1\u03b2, TNF-\u03b1, and MMP-9) and increased that of the anti-inflammatory cytokine IL-10, creating a retinal microenvironment conducive to neuroprotection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study demonstrates that CD3\u03b6 plays a critical role in immune-mediated neurodegeneration in glaucoma. CD3\u03b6 knockdown promotes RGC survival by modulating MAPK and NF-\u03baB signaling pathways and regulating apoptosis and inflammation. These findings underscore the therapeutic potential of targeting TCR signaling to complement existing IOP-lowering treatments, offering a novel approach to preserving visual function in glaucoma.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2025.1652041","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T05:37:27Z","timestamp":1756877847000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["CD3zeta-mediated modulation of TCR signaling: a novel strategy for neuroprotection in retinal ganglion cell degeneration"],"prefix":"10.3389","volume":"13","author":[{"given":"Kexin","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningzhi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenye","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqiao","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"391","DOI":"10.4103\/1673-5374.245465","article-title":"Neuroinflammation as a target for glaucoma therapy","volume":"14","author":"Adornetto","year":"2019","journal-title":"Neural Regen. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1034\/j.1600-065x.2003.00017.x","article-title":"Initiation of TCR signaling: regulation within CD3 dimers","volume":"191","author":"Alarc\u00f3n","year":"2003","journal-title":"Immunol. Rev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"860070","DOI":"10.3389\/fimmu.2022.860070","article-title":"Neuroinflammation, microglia and implications for retinal ganglion cell survival and axon regeneration in traumatic optic neuropathy","volume":"13","author":"Au","year":"2022","journal-title":"Front. Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1091\/mbc.e03-08-0585","article-title":"p38 MAPK-induced nuclear factor-kappaB activity is required for skeletal muscle differentiation: role of interleukin-6","volume":"15","author":"Baeza-Raja","year":"2004","journal-title":"Mol. Biol. Cell."},{"key":"B5","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.expneurol.2015.12.015","article-title":"Reaching the brain: advances in optic nerve regeneration","volume":"287","author":"Benowitz","year":"2017","journal-title":"Exp. Neurol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1146\/annurev-genom-091416-035332","article-title":"Cognitive dysfunctions in intellectual disabilities: the contributions of the Ras-MAPK and PI3K-AKT-mTOR pathways","volume":"18","author":"Borrie","year":"2017","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/s41577-019-0203-y","article-title":"Metabolic coordination of T cell quiescence and activation","volume":"20","author":"Chapman","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.tibs.2017.11.008","article-title":"TCR signaling: mechanisms of initiation and propagation","volume":"43","author":"Courtney","year":"2018","journal-title":"Trends Biochem. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"935367","DOI":"10.3389\/fimmu.2022.935367","article-title":"Negative regulation of Zap70 by Lck forms the mechanistic basis of differential expression in CD4 and CD8 T cells","volume":"13","author":"Damen","year":"2022","journal-title":"Front. Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e13170","DOI":"10.1111\/sji.13170","article-title":"Advances in CD247","volume":"96","author":"Dexiu","year":"2022","journal-title":"Scand. J. Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.3390\/biology12091163","article-title":"A story of kinases and adaptors: the role of Lck, ZAP-70 and LAT in switch panel governing T-cell development and activation","volume":"12","author":"Fern\u00e1ndez-Aguilar","year":"2023","journal-title":"Biology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/s00281-010-0196-x","article-title":"ZAP70: a master regulator of adaptive immunity","volume":"32","author":"Fischer","year":"2010","journal-title":"Semin. Immunopathol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"10896","DOI":"10.3390\/ijms221910896","article-title":"7,8-Dihydroxiflavone protects adult rat axotomized retinal ganglion cells through MAPK\/ERK and PI3K\/AKT activation","volume":"22","author":"Galindo-Romero","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/s41577-018-0020-8","article-title":"Regulatory mechanisms in T cell receptor signalling","volume":"18","author":"Gaud","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"114781","DOI":"10.1016\/j.addr.2023.114781","article-title":"Gene therapy strategies for glaucoma from IOP reduction to retinal neuroprotection: progress towards non-viral systems","volume":"196","author":"Hakim","year":"2023","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B16","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1186\/s13045-019-0812-8","article-title":"Targeting cancers through TCR-peptide\/MHC interactions","volume":"12","author":"He","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2307","DOI":"10.3390\/ijms25042307","article-title":"The role of complement dysregulation in glaucoma","volume":"25","author":"Hoppe","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.1016\/S0140-6736(17)31469-1","article-title":"Glaucoma","volume":"390","author":"Jonas","year":"2017","journal-title":"Lancet"},{"key":"B19","doi-asserted-by":"publisher","first-page":"5037","DOI":"10.1523\/JNEUROSCI.20-13-05037.2000","article-title":"Role of p38 mitogen-activated protein kinase in axotomy-induced apoptosis of rat retinal ganglion cells","volume":"20","author":"Kikuchi","year":"2000","journal-title":"J. Neurosci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"a001651","DOI":"10.1101\/cshperspect.a001651","article-title":"The nuclear factor NF-kappaB pathway in inflammation","volume":"1","author":"Lawrence","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1146\/annurev.immunol.17.1.435","article-title":"The structural basis of T cell activation by superantigens","volume":"17","author":"Li","year":"1999","journal-title":"Annu. Rev. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1007\/s12035-020-02199-4","article-title":"Reactive fibroblasts in response to optic nerve crush injury","volume":"58","author":"Liu","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1038\/s41590-018-0131-1","article-title":"Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT","volume":"19","author":"Lo","year":"2018","journal-title":"Nat. Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"7807","DOI":"10.4049\/jimmunol.174.12.7807","article-title":"Differential Src family kinase activity requirements for CD3 zeta phosphorylation\/ZAP70 recruitment and CD3 epsilon phosphorylation","volume":"174","author":"Lysechko","year":"2005","journal-title":"J. Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"3498","DOI":"10.3390\/ijms21103498","article-title":"Clustering of the \u03b6-chain can initiate T cell receptor signaling","volume":"21","author":"Ma","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1074\/jbc.REV119.009411","article-title":"The structural basis of T-cell receptor (TCR) activation: an enduring enigma","volume":"295","author":"Mariuzza","year":"2020","journal-title":"J. Biol. Chem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2557","DOI":"10.1002\/eji.200737837","article-title":"Reduced Cbl phosphorylation and degradation of the zeta-chain of the T-cell receptor\/CD3 complex in T cells with low Lck levels","volume":"38","author":"Methi","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"4662","DOI":"10.3390\/ijms22094662","article-title":"Vascular aspects in glaucoma: from pathogenesis to therapeutic approaches","volume":"22","author":"Mursch-Edlmayr","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B29","first-page":"3319","article-title":"Brain-derived neurotrophic factor prevents axotomized retinal ganglion cell death through MAPK and PI3K signaling pathways","volume":"43","author":"Nakazawa","year":"2002","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2393","DOI":"10.1167\/iovs.12-9781","article-title":"The pathogenesis of glaucoma in the interplay with the immune system","volume":"54","author":"Rieck","year":"2013","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1146\/annurev-immunol-032414-112334","article-title":"T cell antigen receptor recognition of antigen-presenting molecules","volume":"33","author":"Rossjohn","year":"2015","journal-title":"Annu. Rev. Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1161\/HYPERTENSIONAHA.113.02191","article-title":"CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney","volume":"63","author":"Rudemiller","year":"2014","journal-title":"Hypertension"},{"key":"B33","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.ejphar.2016.03.064","article-title":"Retinal ganglion cell death in glaucoma: exploring the role of neuroinflammation","volume":"787","author":"Russo","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"2069","DOI":"10.14336\/AD.2024.0103","article-title":"Glial cell activation and immune responses in glaucoma: a systematic review of human postmortem studies of the retina and optic nerve","volume":"15","author":"Salkar","year":"2024","journal-title":"Aging Dis."},{"key":"B35","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/S0361-9230(03)00076-5","article-title":"Optic nerve crush: protection and regeneration","volume":"62","author":"Schwartz","year":"2004","journal-title":"Brain Res. Bull."},{"key":"B36","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/s41392-021-00823-w","article-title":"T cell receptor (TCR) signaling in health and disease","volume":"6","author":"Shah","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.3390\/cells10081973","article-title":"Immune responses in the glaucomatous retina: regulation and dynamics","volume":"10","author":"Shestopalov","year":"2021","journal-title":"Cells"},{"key":"B38","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1186\/s12974-024-03075-x","article-title":"Pathological high intraocular pressure induces glial cell reactive proliferation contributing to neuroinflammation of the blood-retinal barrier via the NOX2\/ET-1 axis-controlled ERK1\/2 pathway","volume":"21","author":"Shi","year":"2024","journal-title":"J. Neuroinflammation"},{"key":"B39","first-page":"1540","article-title":"Gamma-synuclein as a marker of retinal ganglion cells","volume":"14","author":"Surgucheva","year":"2008","journal-title":"Mol. Vis."},{"key":"B40","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.coph.2012.09.013","article-title":"Immune regulation toward immunomodulation for neuroprotection in glaucoma","volume":"13","author":"Tezel","year":"2013","journal-title":"Curr. Opin. Pharmacol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"2396","DOI":"10.1128\/MCB.00165-16","article-title":"Phosphorylation of a tyrosine residue on Zap70 by Lck and its subsequent binding via an SH2 domain may be a key gatekeeper of T cell receptor signaling in vivo","volume":"36","author":"Thill","year":"2016","journal-title":"Mol. Cell. Biol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1202704","DOI":"10.3389\/fimmu.2023.1202704","article-title":"Exosome-based crosstalk in glaucoma pathogenesis: a focus on oxidative stress and neuroinflammation","volume":"14","author":"Wang","year":"2023","journal-title":"Front. Immunol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/s41392-020-00312-6","article-title":"Targeting NF-\u03baB pathway for the therapy of diseases: mechanism and clinical study","volume":"5","author":"Yu","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"B44","doi-asserted-by":"publisher","first-page":"112185","DOI":"10.1016\/j.celrep.2023.112185","article-title":"NF-\u03baB activation enhances STING signaling by altering microtubule-mediated STING trafficking","volume":"42","author":"Zhang","year":"2023","journal-title":"Cell Rep."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2025.1652041\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T05:37:28Z","timestamp":1756877848000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2025.1652041\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,3]]},"references-count":44,"alternative-id":["10.3389\/fcell.2025.1652041"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2025.1652041","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,3]]},"article-number":"1652041"}}