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Diabetes. 2019 Aug 1. pii: db190239. doi: 10.2337/db19-0239. [Epub ahead of print]

CCL21 Expression in β-Cells Induces Antigen-Expressing Stromal Cell Networks in the Pancreas and Prevents Autoimmune Diabetes in Mice.

Author information

1
Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
2
Department of Biomedical Engineering, University of Miami, Miami, FL, USA.
3
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA.
4
Institute of Physiological Chemistry and Pathobiochemistry and Cells in Motion (CiM), Cluster of Excellence, University of Muenster, Muenster, Germany.
5
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Miami Miller School of Medicine, Miami, Florida, USA.
6
Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA atomei@miami.edu.
7
Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.

Abstract

Tumors induce tolerance towards their antigens by producing the chemokine CCL21, leading to the formation of tertiary lymphoid organs (TLOs). Ins2-CCL21 transgenic, non-obese diabetic (NOD) mice express CCL21 in pancreatic β-cells and do not develop autoimmune diabetes. We investigated by which mechanisms CCL21 expression prevented diabetes. Ins2-CCL21 mice develop TLOs by 4 weeks of age consisting of naïve CD4+ T cells compartmentalized within networks of CD45- gp38+ CD31- fibroblastic reticular cell (FRC)-like cells. Importantly, 12 week-old Ins2-CCL21 TLOs contained FRC-like cells with higher contractility, regulatory, and anti-inflammatory properties and enhanced expression of β-cell autoantigens compared to non-transgenic NOD TLOs found in inflamed islets. Consistently, transgenic mice harbored fewer autoreactive T cells and higher proportion of Tregs in the islets. Using adoptive transfer and islet transplantation models, we demonstrate that TLO formation in Ins2-CCL21 transgenic islets is critical for regulation of autoimmunity and while the effect is systemic, the induction is mediated locally likely by lymphocyte trafficking through TLOs. Overall, our findings suggest that CCL21 promotes TLOs that differ from inflammatory TLOs found in T1D islets in that they resemble lymph nodes, contain FRC-like cells expressing β-cell autoantigens and are able to induce systemic and antigen-specific tolerance leading to diabetes prevention.

PMID:
31371518
DOI:
10.2337/db19-0239

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