Abstract
T cells and B cells have been identified in human and murine islets, but the phenotype and role of islet lymphocytes is unknown. Resident immune populations set the stage for responses to inflammation in the islets during homeostasis and diabetes. Thus, we sought to identify the phenotype and effector function of islet lymphocytes to better understand their role in normal islets and in islets under metabolic stress. Lymphocytes were located in the islet parenchyma, and were comprised of a mix of naïve, activated, and memory T cell and B cell subsets, with an enrichment for regulatory B cell subsets. Use of a Nur77 reporter indicated that CD8 T cells and B cells both received local antigen stimulus, indicating that they responded to antigens present in the islets. Analysis of effector function showed that islet T cells and B cells produced the regulatory cytokine IL-10. The regulatory phenotype of islet T cells and B cells and their response to local antigenic stimuli remained stable under conditions of metabolic stress in the diet induced obesity (DIO) model. T cells present in human islets retained a similar activated and memory phenotype in non-diabetic and T2D donors. Under steady-state conditions, islet T cells and B cells have a regulatory phenotype, and thus may play a protective role in maintaining tissue homeostasis.
Highlights
There is increasing evidence that islet inflammation occurs in autoimmune type 1 diabetes (T1D), and in type 2 diabetes (T2D) [1, 2]
We determined that T cells and B cells were primarily located in the islet parenchyma by generating a threedimensional vascular surface based on CD31 staining and classifying the T cell and B cell localization relative to the vasculature (Figures 1D, E)
Our results indicate that islet T cells and B cells receive local antigen stimulus and express a regulatory phenotype in normal and pre-T2D islets
Summary
There is increasing evidence that islet inflammation occurs in autoimmune type 1 diabetes (T1D), and in type 2 diabetes (T2D) [1, 2]. T2D islets contain an increased number of macrophages compared to non-diabetic islets [2, 5]. Obesity is a common comorbidity with T2D patients [6], which can be associated with adipose tissue inflammation that results in increased circulating pro-inflammatory cytokines such as TNFa and IL-6 [6, 7]. Because islets are highly vascularized, the islet environment is sensitive to circulating and local cytokines. In T2D, islet macrophages convert from an anti-inflammatory M2 state to M1-like phenotype and
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