Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 14, Pages 3708-3713Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1700878114
Keywords
type I interferon; IFN-alpha; S1PR1; type 1 diabetes
Categories
Funding
- NIH [AI009484, 5T32AI007354-2, 5T32AI007244-33]
- Jeanette Bertea Hennings Foundation
- Skaggs-Oxford Scholarship
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Blockade of IFN-alpha but not IFN-beta signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouse Rip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune anti-self 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 beta cells. Second, CYM-5442 induced an exhaustion signature in antiself T cells by up-regulating the negative immune regulator receptor genes Pdcd1, Lag3, Ctla4, Tigit, and Btla, thereby limiting their killing ability. By such means, insulin production was preserved and glucose regulation maintained, and a mechanism for S1PR1 immunomodulation described.
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