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 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.
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA.
Reiko
R
Horai
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA.
Carlos R
CR
Zárate-Bladés
Oral and Pharyngeal Cancer Branch, National Institutes of Dental and Craniofacial Research, NIH, Bethesda, MD 20892, USA.
Patricia
P
Dillenburg-Pilla
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA; State Key of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
Jun
J
Chen
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA.
Jennifer L
JL
Kielczewski
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA.
Phyllis B
PB
Silver
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA.
Yingyos
Y
Jittayasothorn
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA.
Chi-Chao
CC
Chan
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
Hidehiro
H
Yamane
Keio University School of Medicine, Tokyo 160-8582, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
Kenya
K
Honda
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA. Electronic address: caspir@mail.nih.gov.
Rachel R
RR
Caspi
D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D001813:Blood-Retinal Barrier / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance; D007422:Intestines / Q000276:immunology* / Q000382:microbiology; D008213:Lymphocyte Activation; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D064307:Microbiota / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012160:Retina / Q000276:immunology*; D012177:Retinol-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014605:Uveitis / Q000276:immunology* / Q000382:microbiology; D000099214:Retinol-Binding Proteins, Interstitial
D000942:Antigens, Bacterial; D001324:Autoantigens; D005136:Eye Proteins; D011948:Receptors, Antigen, T-Cell; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial