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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Altered microbial composition has been associated with neovascularization and immune cell activation in retinal disease models.
“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]
Autoreactive T cells respond to stimulation with cecal content.
“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]
Cross-reactivity to unidentified commensal antigens triggers an autoimmune response in the R161H mouse model.
“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]
Antibiotic treatment delays the onset of uveitis in R161H mice.
“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]
Effector autoreactive T cells are detectable in R161H mice lacking RBP3, especially in the intestinal lamina propria, indicating a nonendogenous source of cognate peptide.
“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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Can Gut Microbiota Affect Dry Eye Syndrome?
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Gut mycobiomes are altered in people with type 2 Diabetes Mellitus and Diabetic Retinopathy
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The role of the gut microbiome in eye diseases
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Relationship between the microbiome and ocular health
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Protection of Fecal Microbiota Transplantation in a Mouse Model of Multiple Sclerosis
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The Role of Microbiota in Retinal Disease
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New insights into mononuclear phagocyte biology from the visual system
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The Gut–CNS Axis in Multiple Sclerosis
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The microbiome of the built environment and mental health
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T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity
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Autoimmune Disorders of the Nervous System: Pathophysiology, Clinical Features, and Therapy
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Alterations in the gut bacterial microbiome in fungal Keratitis patients
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The microbiome and ophthalmic disease
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The gut-eye-lacrimal gland-microbiome axis in Sjögren Syndrome
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Ocular Microbiota and Intraocular Inflammation
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Recent Developments in HLA B27 Anterior Uveitis
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The role of the intestinal microbiome in ocular inflammatory disease
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Gut Microbiota Influence in Hematological Malignancies: From Genesis to Cure
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Gut microbiome and autoimmune disorders
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Re-examining the Nature and Function of Self-Reactive T cells
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Gut microbiome dysbiosis alleviates the progression of osteoarthritis in mice.
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Microbiota and Ocular Diseases
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Novel perspectives on therapeutic modulation of the gut microbiota
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Intestinal Permeability in Relapsing-Remitting Multiple Sclerosis
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The Microbiota Determines Susceptibility to Experimental Autoimmune Uveoretinitis
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Circadian Host-Microbiome Interactions in Immunity
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A dynamic atlas of immunocyte migration from the gut
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Gut microbiota-dependent CCR9+CD4+ T cells are altered in secondary progressive multiple sclerosis
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Impact of gut microbiota on gut‐distal autoimmunity: a focus on T cells
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Alterations in the Ocular Surface Fungal Microbiome in Fungal Keratitis Patients
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Gut Microbial Antigenic Mimicry in Autoimmunity
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Gut Microbiota and Salivary Diagnostics: The Mouth Is Salivating to Tell Us Something
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Metagenomics in ophthalmology: current findings and future prospectives
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Dry Eye Disease: Emerging Approaches to Disease Analysis and Therapy
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Gut inflammation promotes microbiota-specific CD4 T cell-mediated neuroinflammation
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- 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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