Progression of type 1 diabetes from the prediabetic stage is controlled by interferon-α signaling.
Blockade of IFN-α but not IFN-β signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouseRip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune "antiself" T cells to the external boundaries around the islets and prevented their entry into the islets so they could not be positioned to engage, kill, and thus remove insulin-producing β cells. Second, CYM-5442 induced an exhaustion signature in antiself T cells by up-regulating the negative immune regulator receptor genesPdcd1, Lag3, Ctla4, Tigit, andBtla, thereby limiting their killing ability. By such means, insulin production was preserved and glucose regulation maintained, and a mechanism for S1PR1 immunomodulation described.
Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
Brett S
BS
Marro
Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
Brian C
BC
Ware
Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.|Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
Jaroslav
J
Zak
Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
Juan Carlos
JC
de la Torre
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
Hugh
H
Rosen
Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; mbaobo@scripps.edu.
Michael B A
MB
Oldstone
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D007189:Indans / Q000008:administration & dosage* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000276:immunology; D016898:Interferon-alpha / Q000378:metabolism*; D007515:Islets of Langerhans / Q000276:immunology; D051379:Mice; D010069:Oxadiazoles / Q000008:administration & dosage* / Q000494:pharmacology; D011236:Prediabetic State / Q000188:drug therapy* / Q000276:immunology; D011971:Receptors, Immunologic / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D000081025:Sphingosine-1-Phosphate Receptors; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
C532995:2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino)ethanol; D007189:Indans; D007328:Insulin; D016898:Interferon-alpha; D010069:Oxadiazoles; D011971:Receptors, Immunologic; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors
IFN-alpha; S1PR1; type 1 diabetes; type I interferon