Immune Landscape and Intercellular Crosstalk in the Cornea of an Autoimmune-Mediated Dry Eye Disease.
- 1Program in Craniofacial Biology, Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, California, United States.
- 2School of Optometry and Vision Science Graduate Program, University of California - Berkeley, Oakland, California, United States.
- 3Department of Anatomy, University of California - San Francisco, San Francisco, California, United States.
Abstract
Purpose
The purpose of this study was to comprehensively characterize the identity and signaling profiles of resident and infiltrating immune cells, and their interactions with non-immune cells, in a spontaneous mouse model of autoimmune-mediated dry eye disease (DED).Methods
Corneal tissues from wild-type (WT) and autoimmune regulator-deficient (Aire-/-) mice were analyzed by whole-mount immunofluorescence to define immune cell composition and spatial distribution within the limbus and central cornea. Immune cell identities and cell-cell communication were further characterized using single-cell RNA sequencing (scRNA-seq). Intercellular signaling pathways among immune cells, epithelial, and stromal cells were analyzed using CellChat.Results
Immunofluorescence revealed extensive infiltration of CD3⁺ and CD4⁺ T cells, CD45R⁺ B-cells, and IBA1⁺ macrophages in Aire-/- cornea compared with WT controls. The scRNA-seq identified diverse immune subsets, including cytotoxic T cells, γδ17 cells, regulatory T cells, NK T cells, B-cells, plasma cells, and multiple macrophage subtypes. Monocyte-derived macrophages demonstrated distinct transcriptional programs, including pro-inflammatory and antigen-presenting phenotypes, with CD40 to CD40L signaling linking T cells, B-cells, and macrophages. CellChat analysis revealed coordinated upregulation of signaling pathways associated with immune activation, inflammation, apoptosis, and loss of immune tolerance. Additionally, epithelial cells and keratocytes in Aire-/- corneas upregulated antigen-presenting and pro-inflammatory gene signatures, suggesting active participation of non-immune cells in immune activation and recruitment.Conclusions
Single-cell transcriptomics reveals a complex, multicellular inflammatory environment in the Aire-/- cornea involving diverse immune subsets and activated resident epithelial and stromal cells. These findings suggest that non-T cell mechanisms contribute to chronic dry eye pathogenesis and may underlie the limited efficacy of currently US Food and Drug Administration (FDA)-approved T cell-targeted therapies. Further characterization of these multi-cellular interactions and signaling pathways may inform the development of broader therapeutic strategies for autoimmune-mediated dry eye disease.
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BibTeX
@article{an2026immune,
title = {{Immune Landscape and Intercellular Crosstalk in the Cornea of an Autoimmune-Mediated Dry Eye Disease.}},
author = {Luye An and Mario A Robledo and Seyyed Vahid Niknezhad and Wendy Ko and Beryl Zhang and Yu Ting Chen and Nancy A McNamara and Sarah M Knox},
journal = {Investigative ophthalmology \& visual science},
year = {2026},
month = oct,
doi = {10.1167/iovs.67.12.32},
url = {https://europepmc.org/article/MED/42885991},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Immune Landscape and Intercellular Crosstalk in the Cornea of an Autoimmune-Mediated Dry Eye Disease.
AU - Luye An
AU - Mario A Robledo
AU - Seyyed Vahid Niknezhad
AU - Wendy Ko
AU - Beryl Zhang
AU - Yu Ting Chen
AU - Nancy A McNamara
AU - Sarah M Knox
PY - 2026
DA - 2026/10/01
JO - Investigative ophthalmology & visual science
DO - 10.1167/iovs.67.12.32
UR - https://europepmc.org/article/MED/42885991
AB - Purpose The purpose of this study was to comprehensively characterize the identity and signaling profiles of resident and infiltrating immune cells, and their interactions with non-immune cells, in a spontaneous mouse model of autoimmune-mediated dry eye disease (DED).Methods Corneal tissues from wild-type (WT) and autoimmune regulator-deficient (Aire-/-) mice were analyzed by whole-mount immunofluorescence to define immune cell composition and spatial distribution within the limbus and central cornea. Immune cell identities and cell-cell communication were further characterized using single-cell RNA sequencing (scRNA-seq). Intercellular signaling pathways among immune cells, epithelial, and stromal cells were analyzed using CellChat.Results Immunofluorescence revealed extensive infiltration of CD3⁺ and CD4⁺ T cells, CD45R⁺ B-cells, and IBA1⁺ macrophages in Aire-/- cornea compared with WT controls. The scRNA-seq identified diverse immune subsets, including cytotoxic T cells, γδ17 cells, regulatory T cells, NK T cells, B-cells, plasma cells, and multiple macrophage subtypes. Monocyte-derived macrophages demonstrated distinct transcriptional programs, including pro-inflammatory and antigen-presenting phenotypes, with CD40 to CD40L signaling linking T cells, B-cells, and macrophages. CellChat analysis revealed coordinated upregulation of signaling pathways associated with immune activation, inflammation, apoptosis, and loss of immune tolerance. Additionally, epithelial cells and keratocytes in Aire-/- corneas upregulated antigen-presenting and pro-inflammatory gene signatures, suggesting active participation of non-immune cells in immune activation and recruitment.Conclusions Single-cell transcriptomics reveals a complex, multicellular inflammatory environment in the Aire-/- cornea involving diverse immune subsets and activated resident epithelial and stromal cells. These findings suggest that non-T cell mechanisms contribute to chronic dry eye pathogenesis and may underlie the limited efficacy of currently US Food and Drug Administration (FDA)-approved T cell-targeted therapies. Further characterization of these multi-cellular interactions and signaling pathways may inform the development of broader therapeutic strategies for autoimmune-mediated dry eye disease.
SN - 0146-0404
SN - 1552-5783
ER -