Differentiating MHC-Dependent and -Independent Mechanisms of Lymph Node Stromal Cell Regulation of Proinsulin-Specific CD8+ T-Cells in type 1 Diabetes

Abstract Context There are scant reports on the pathological changes of the exocrine and endocrine pancreas in fulminant type 1 diabetes mellitus (FT1DM). Objective To clarify the distinct pathological changes in the exocrine as well as the endocrine pancreas shortly after onset of diabetes in FT1DM. Design The exocrine and endocrine pancreases of 3 patients with FT1DM and 17 nondiabetic controls were immunohistochemically examined for islet and exocrine tissue inflammation, infiltrating mononuclear cell (MNC) CD subtype, enterovirus capsid protein 1 (VP1) localization, and CXC chemokine ligand 10 (CXCL10) and CXC chemokine receptor 3 (CXCR3) expressions. Results The median frequency of insulitis in the 3 FT1DM pancreases was 60%. In the nondiabetic control pancreases, no insulitis was observed. In the islets of FT1DM, the numbers of CD45+, CD3+, CD8+, CD68+, and CD11c+ MNCs were significantly higher than those of the control group. In the exocrine pancreas of FT1DM, the numbers of CD3+ T cells, CD8+ T cells, CD68+ macrophages, and CD11c+ dendritic cells were significantly higher than those of the control group. Infiltrating CD8+ T cells, CD68+ macrophages, and CD11c+ dendritic cells were observed around exocrine acinar cells in FT1DM. There was a close association between VP1 and CXCL10 expression in pancreatic exocrine ductal cells and acinar cells as well as islet cells in FT1DM. CXCL10+ exocrine cells were surrounded by CXCR3+ T cells. Conclusion The pathological findings suggested that suppression of the activated CXCL10–CXCR3 axis in the exocrine as well as the endocrine pancreas is a novel therapeutic target in FT1DM and possibly in enterovirus-associated acute-onset type 1 diabetes.

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PD-1 and PD-L1 Expression in Peripheral CD4/CD8+ T Cells Is Restored in the Partial Remission Phase in Type 1 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa130 ◽

2020 ◽

Vol 105 (6) ◽

pp. 1947-1956 ◽

Cited By ~ 2

Author(s):

Xia Li ◽

Ting Zhong ◽

Rong Tang ◽

Chao Wu ◽

Yuting Xie ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Cd8 T Cells ◽

Partial Remission ◽

Dynamic Change ◽

Dynamic Changes ◽

Programmed Cell Death 1 ◽

Remission Phase ◽

Expression Frequency

Abstract Context Partial remission (PR) in type 1 diabetes (T1D) is accompanied by downregulation of the immune response. Programmed cell death-1 (PD-1) and its ligand (PD-L1) are important immunosuppressive molecules, but their changes in the PR phase are unclear. Objective We investigated the dynamic changes of PD-1/PD-L1 expression on T cells around the PR phase in T1D. Methods Ninety-eight T1D patients were recruited cross-sectionally and grouped according to PR status into nonremitters (individuals who did not undergo PR during the disease course; n = 39), pre-PR (n = 15), mid-PR (n = 30), and post-PR (n = 14) subgroups. PR was defined according to C-peptide level ≥300 pmol/L or index of insulin-adjusted hemoglobin A1c ≤9 as recommended. Among all the 98 patients, 29 newly diagnosed individuals were prospectively followed up for 1 year. The dynamic changes of PD-1/PD-L1 expression, frequency of regulatory T cells (Tregs) and IL-35+ Tregs among peripheral CD4/CD8+ T cells were determined. Results PD-1/PD-L1 on CD4+/CD8+ T cells showed a dynamic change around the PR phase: lowest in pre-PR phase, restored in mid-PR phase, and declined again in post-PR phase. Conversely, this pattern did not occur for nonremitters. Notably, PD-1 expression on CD8+ T cells in mid-PR was positively correlated with the length of the PR phase. The percentages of circulating Tregs and IL-35+ Tregs showed no relation to PR. Conclusions The PR phase is associated with restoration of PD-1/PD-L1 on CD4+ and CD8+ T cells, suggesting that PD-1/PD-L1 may be a potential target for prolonging this phase in T1D.

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