Impaired regulatory T cell mediated immune tolerance promotes neurodegeneration in glaucoma
- 1University of Iowa
Abstract
Neurodegenerative diseases are increasingly recognized to involve detrimental interactions between the immune and nervous systems, yet whether failure of peripheral immune tolerance actively drives neuronal loss frequently remains unclear. 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-mediated 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.
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BibTeX
@misc{zeng2026impaired,
title = {{Impaired regulatory T cell mediated immune tolerance promotes neurodegeneration in glaucoma}},
author = {H. Zeng and M.-G. Jones and Z. Zacharias and E. A. Boese and W. L. M. Alward and Y. H. Kwon and J. C. Houtman and E. Linton and R. H. Kardon and O. W. Gramlich and M. Kuehn},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.26363354},
url = {https://www.medrxiv.org/content/10.64898/2026.09.17.26363354v1},
note = {Public domain},
}
RIS
TY - UNPB
TI - Impaired regulatory T cell mediated immune tolerance promotes neurodegeneration in glaucoma
AU - H. Zeng
AU - M.-G. Jones
AU - Z. Zacharias
AU - E. A. Boese
AU - W. L. M. Alward
AU - Y. H. Kwon
AU - J. C. Houtman
AU - E. Linton
AU - R. H. Kardon
AU - O. W. Gramlich
AU - M. Kuehn
PY - 2026
DA - 2026/09/17
PB - medRxiv
DO - 10.64898/2026.09.17.26363354
UR - https://www.medrxiv.org/content/10.64898/2026.09.17.26363354v1
AB - Neurodegenerative diseases are increasingly recognized to involve detrimental interactions between the immune and nervous systems, yet whether failure of peripheral immune tolerance actively drives neuronal loss frequently remains unclear. 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-mediated 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.
ER -