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| Status |
Public on Sep 23, 2019 |
| Title |
CCL21 Expression in Beta Cells Induces Antigen-Expressing Stromal Cell Networks in the Pancreas and Prevents Autoimmune Diabetes in Mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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. Islet infiltrates of 4 week-old Ins2-CCL21 mice were enriched in naïve CD4+ T cells and compartmentalized within networks of CD45- gp38+ CD31- fibroblastic reticular cell (FRC)-like stromal cells. Importantly, 12 week-old Ins2-CCL21 NOD islets contained FRC-like cells with enhanced expression of β-cell autoantigens and gene expression profiles consistent with regulatory, anti-inflammatory properties and increased contractility. 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 the formation of TLOs in Ins2-CCL21 transgenic islets is critical for regulation of autoimmunity and while the effect is systemic, the induction may be mediated locally by lymphocyte trafficking through TLOs. Overall, our findings suggest that CCL21 promotes TLOs that differ from inflammatory TLOs associated with islets in T1D 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. These findings suggest that CCL21 may be exploited for novel immunoregulation approaches to treat autoimmune diabetes.
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| Overall design |
Examination of lymph node derived Fibroblastic Reticular Cells (FRCs), FRC-like cells from pancreatic islets and islet infiltrating leukocytes in both Ins2-CCL21 transegnic NOD (TG+ samples) and non-transgenic NOD (TG- samples) mice
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| Contributor(s) |
Gonzalez Badillo F, Zisi Tegou F, Griswold AJ, Tomei A |
| Citation(s) |
31371518 |
| |
| Submission date |
May 09, 2019 |
| Last update date |
Sep 25, 2019 |
| Contact name |
Anthony Griswold |
| E-mail(s) |
agriswold@med.miami.edu
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| Organization name |
University of Miami
|
| Street address |
1501 NW 10th Ave, BRB 318
|
| City |
Miami |
| State/province |
FL |
| ZIP/Postal code |
33136 |
| Country |
USA |
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| Platforms (1) |
| GPL21493 |
Illumina HiSeq 3000 (Mus musculus) |
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| Samples (27)
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| Relations |
| BioProject |
PRJNA542161 |
| SRA |
SRP197377 |
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