Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site

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 ant...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2015-08, Vol.43 (2), p.343-353
Main Authors: Horai, Reiko, Zárate-Bladés, Carlos R., Dillenburg-Pilla, Patricia, Chen, Jun, Kielczewski, Jennifer L., Silver, Phyllis B., Jittayasothorn, Yingyos, Chan, Chi-Chao, Yamane, Hidehiro, Honda, Kenya, Caspi, Rachel R.
Format: Article
Language:English
Subjects:
Age
Animals
Antigens
Antigens, Bacterial - administration & dosage
Autoantigens - immunology
Autoimmunity
Blood-Retinal Barrier - immunology
Cells, Cultured
Disease
Disease Models, Animal
Eye Proteins - genetics
Eye Proteins - immunology
Eye Proteins - metabolism
Genotype & phenotype
Histology
Immune system
Immune Tolerance
Intestines - immunology
Intestines - microbiology
Laboratories
Lymphatic system
Lymphocyte Activation
Lymphocytes
Medical research
Mice, Inbred Strains
Mice, Knockout
Microbiota - immunology
Microorganisms
Receptors, Antigen, T-Cell - metabolism
Retina - immunology
Retinol-Binding Proteins - genetics
Retinol-Binding Proteins - immunology
Retinol-Binding Proteins - metabolism
Software
T cell receptors
T-Lymphocytes - immunology
Uveitis - immunology
Uveitis - microbiology
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Summary: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. [Display omitted] •T cell activation in the gut correlates with spontaneous uveitis in R161H mice•Elimination of gut microbiota attenuates disease and reduces T cell activation in the gut•Presence of endogenous antigen is not required for intestinal T cell activation•Extracts of intestinal contents signal via retina-specific TCR and trigger uveitis It is unknown where and how T cells reactive to self antigens residing behind blood-tissue barriers first become activated. Caspi and colleagues show that retina-specific T cells receive an activation signal in the gut from a crossreactive antigen dependent on commensal microbiota and trigger autoimmunity in the eye.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2015.07.014