Denroche, H. C. | bioRxiv Science

bioRxiv2024

Islet amyloid disrupts MHC Class II antigen presentation and protects NOD mice from autoimmune diabetes.

Islet amyloid contributes to beta cell failure in type 2 diabetes through several mechanisms, one being the potent induction of local islet inflammation through activating inflammatory pathways in islet macrophages. We performed an unbiased phenotypic investigation of islet macrophages in the early stage of islet amyloid formation using single cell RNA sequencing of resident islet macrophages in mice with and without the amyloidogenic form of human islet amyloid polypeptide (hIAPP). This revealed that MHC Class II antigen presentation genes were strongly down-regulated in islet macrophages during islet amyloid formation. As islet amyloid has recently been reported in pancreases of people with type 1 diabetes, we sought to investigate the impact of islet amyloid in the NOD mouse model of type 1 diabetes. Both overexpression and physiological expression of hIAPP delayed diabetes in NOD mice relative to littermate controls, corresponding with decreased markers of antigen presentation and activation, as well as decreased immune cell infiltration in islets. Adoptive transfer studies showed that systemic autoimmune function remained intact and beta cells from hIAPP transgenic mice did not evade immune recognition by diabetogenic T cells, collectively indicating the protection from diabetes was mediated by localized disruption of antigen presentation in the pancreas. Consistent with this, incubation of dendritic cells with IAPP aggregates decreased MHC Class II surface expression and diminished antigen-specific T cell activation in vitro, through a phagocytosis-dependent mechanism. Collectively our data show that despite the well-established pro-inflammatory response of macrophages to IAPP aggregates, the uptake of IAPP aggregates during early amyloid formation also disrupts MHC Class II antigen presentation and slows beta cell autoimmunity.

immunology↗

bioRxiv2020

T cells are present in non-diabetic islets and accumulate during aging.

BackgroundThe resident immune population of pancreatic islets has roles in islet development, beta cell physiology, and the pathology of diabetes. These roles have largely been attributed to islet macrophages, comprising 90% of islet immune cells (in the absence of islet autoimmunity), and, in the case of type 1 diabetes, to infiltrating autoreactive T cells. In adipose, tissue-resident and recruited T and B cells have been implicated in the development of insulin resistance during diet-induced obesity and aging, but whether this is paralleled in the pancreatic islets is not known. Here, we investigated the non-macrophage component of resident islet immune cells in islets isolated from C57BL/6J male mice during aging (3 to 24 months of age) and following diet-induced obesity (12 weeks 60% high fat diet). Immune cells were also examined by flow cytometry in cadaveric non-diabetic human islets. ResultsImmune cells comprised 2.7 {+/-} 1.3% of total islet cells in non-diabetic mouse islets, and 2.3 {+/-} 1.7% of total islet cells in non-diabetic human islets. In 3-month old mice on standard diet, B and T cells each comprised approximately 2-4% of the total islet immune cell compartment, and approximately 0.1% of total islet cells. A similar amount of T cells were present in non-diabetic human islets. Islet T cells were comprised of CD8-positive, CD4-positive, and regulatory T cells. Interestingly, while islet B cells and macrophage numbers were unaltered by age, the number of islet T cells increased linearly (R2=0.9902) with age from 0.10 {+/-} 0.05% (3 months) to 0.38 {+/-}0.11% (24 months) of islet cells. This increase was uncoupled from body weight, and was not phenocopied by a degree similar weight gain induced by high fat diet in mice. ConclusionsThis study reveals that T cells are a part of the normal islet immune population in mouse and human islets, and that they accumulate in islets during aging in a body weight-independent manner. Though comprising only a small subset of the immune cells within islets, islet T cells may play a role in the physiology of islet aging.

physiology↗