Document Type

Article

Publication Date

12-3-2019

Keywords

JMG

JAX Source

Cell Rep 2019 Dec 3; 29(10):3073-3086.e5

Volume

29

Issue

10

First Page

3073

Last Page

3086

ISSN

2211-1247

PMID

31801074

DOI

https://doi.org/10.1016/j.celrep.2019.11.010

Grant

DK46266, DK 95735, OD020351

Abstract

Human genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27Rα. In contrast to wild-type NOD mice, both NOD.Il27-/- and NOD.Il27ra-/- strains are completely resistant to T1D. IL-27 from myeloid cells and IL-27 signaling in T cells are critical for T1D development. IL-27 directly alters the balance of regulatory T cells (Tregs) and T helper 1 (Th1) cells in pancreatic islets, which in turn modulates the diabetogenic activity of CD8 T cells. IL-27 also directly enhances the effector function of CD8 T cells within pancreatic islets. In addition to T1D, IL-27 signaling in T cells is also required for lacrimal and salivary gland inflammation in NOD mice. Our study reveals that IL-27 contributes to autoimmunity in NOD mice through multiple mechanisms and provides substantial evidence to support its pathogenic role in human T1D.

Comments

We thank The Jackson Laboratory Genetic Engineering Technologies group for technical support on this project.

This article is available under the Creative Commons CC-BY-NC-ND license

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