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

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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE130979 | GEO | 2019/09/23

REPOSITORIES: GEO

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Project description:Objective: An altered gut bacterial composition is associated with the pathogenesis of type 1 diabetes and short-chain fatty acids are known to play a pivotal role in maintaining gut homeostasis. The effects of short-chain fatty acids on pancreatic islet cell function, insulin production and local immune-infiltration, however, remain elusive.Methods: Five-week-old female NOD mice were fed with an acetylated and butyrylated high-amylose maize-resistant starch (HAMSAB) or control diet for five consecutive weeks. The pancreata were harvested, islets isolated using collagenase, and dispersed into single cells by trypsin. Single-cell RNA sequencing was performed with 10x Chromium. The raw counts were analysed using RStudio with the Seurat package. Human embryonic stem cell-differentiated beta-like cells, mouse islets and INS-1E beta cell line were treated with acetate, butyrate and/or combination. Pro-inflammatory cytokines (IFN- + IL-1) were used for stress response and viability assays. Results: single-cell RNA sequencing analysis mapped the gene expression profiles of 4,301 and 4,113 individual islet cells from HAMSAB or HAMS fed mice, respectively. Cells were annotated into 11 clusters: 5 immune, 4 endocrine, acinar and endothelial cell types. The scRNA seq dataset indicated that T cells, B cells, macrophages, and dendritic cell subsets infiltrated the islets of Langerhans from both HAMSAB and HAMS-fed mice. Interestingly, HAMSAB induced an immune tolerogenic profile and lower cytotoxic Gzma+ CD8+ T cells. Moreover, HAMSAB maintained the expression of beta cell functional genes (i.e., Ins1, Ins2, G6pc2, Prlr and Iapp) and decreased the expression of genes associated with cellular stress (i.e., Fos, Impact, Stat1, Dusp1 and Hsp40/Dnajb1). Short-chain fatty acid treatment decreased pro-inflammatory cytokine-induced stress in mouse islets and INS-1E beta cells. In addition, HAMSAB preserved the identity of endocrine cells, evaluated by a decrease in dedifferentiated poly-hormonal cells expressing endocrine progenitor genes (MafA, Nfix). Importantly, short-chain fatty acids increased insulin levels in human embryonic stem cell-differentiated beta-like cells and improve transplantation outcome in NOD/SCID mice. Conclusions: Short-chain fatty acids prevent diabetes development in NOD mice, at least in part, by enhancing beta cell function and preserving the cell identity of endocrine cells under inflammatory-mediated autoimmune stress.

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

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