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Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site
Open accessAbstract
Activated retina-specific T cells that have acquired the ability to break through the blood-retinal barrier are thought to be causally involved in autoimmune uveitis, a major cause of human blindness. It is unclear where these autoreactive T cells first become activated, given that their cognate antigens are sequestered within the immune-privileged eye. We demonstrate in a novel mouse model of spontaneous uveitis that activation of retina-specific T cells is dependent on gut commensal microbiota. Retina-specific T cell activation involved signaling through the autoreactive T cell receptor (TCR) in response to non-cognate antigen in the intestine and was independent of the endogenous retinal autoantigen. Our findings not only have implications for the etiology of human uveitis, but also raise the possibility that activation of autoreactive TCRs by commensal microbes might be a more common trigger of autoimmune diseases than is currently appreciated.
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In the citing paper
“The altered microbial composition has also been associated with neovascularization and immune cell activation in retinal disease models [4, 50, 99].”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [50]
In the citing paper
“Autoreactive T cells responded to stimulation with cecal content.”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [80]
In the citing paper
“Recent data have emerged to suggest that cross-reactivity to unidentified commensal antigens triggers an autoimmune response in this model [80].”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [80]
In the citing paper
“Importantly, the onset of uveitis in R161H mice could be delayed upon antibiotic treatment [80].”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [80]
In the citing paper
“Indeed, effector auto-reactive T cells could be detected in R161H mice lacking RBP3 as well, especially in the intestinal LP, suggesting a nonendogenous source for cognate peptide.”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [80]
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Metadata
- Authors
- Horai, R., Zárate-Bladés, C. R., Dillenburg-Pilla, P., Chen, J., Kielczewski, J. L., Silver, P. B., Jittayasothorn, Y., Chan, C.-C., Yamane, H., Honda, K., & Caspi, R. R.
- Affiliations
- National Institutes of Health (US)
- Keio University (JP)
- Corresponding author
- Caspi, Rachel R.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 43
- Issue
- 2
- Pages
- 343-353
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC4544742
- OpenAlex
- W1913779731
- Cited by
- 402
- References
- 41
- Citations by year
- 2026: 24 · 2025: 27 · 2024: 30 · 2023: 38 · 2022: 46 · 2021: 40 · 2020: 46 · 2019: 39 · 2018: 32 · 2017: 34 · 2016: 40 · 2015: 6
- FWCI
- 35.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NEI (EY000184)
- CREST, Japan Science and Technology Agency (Tokyo, Japan)
- Topics
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- autoimmune uveitis, T cell activation, blood-retinal barrier, immunologically privileged sites, autoimmunity
- MeSH terms
- Retinol-Binding Proteins, Interstitial, Animals, Antigens, Bacterial, Autoantigens, Blood-Retinal Barrier, Cells, Cultured, Disease Models, Animal, Eye Proteins, Immune Tolerance, Intestines, Lymphocyte Activation, Mice, Inbred Strains, Receptors, Antigen, T-Cell, Retina, Retinol-Binding Proteins, T-Lymphocytes, Uveitis, Autoimmunity, Mice, Knockout, Microbiota
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