# Islet amyloid disrupts MHC class II antigen presentation and delays autoimmune diabetes in NOD mice

## TL;DR

Islet amyloid disrupts immune presentation in mice, delaying diabetes onset despite causing inflammation.

## Contribution

Islet amyloid is shown to delay autoimmune diabetes by inhibiting MHC class II antigen presentation in macrophages.

## Key findings

- Islet amyloid formation downregulates MHC class II antigen presentation genes in macrophages.
- NOD mice expressing hIAPP transgene or knockin show delayed diabetes onset compared to controls.
- IAPP aggregates reduce MHCII surface expression and T cell activation in dendritic cells.

## Abstract

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. As islet amyloid has recently been reported in pancreases of people with type 1 diabetes, and islet macrophages are thought to play a role in the pathogenesis of type 1 diabetes, we sought to understand the impact of islet amyloid on islet macrophages and beta cell autoimmunity.

We performed an unbiased phenotypic investigation of islet macrophages in the early stage of islet amyloid formation using single-cell RNA-seq of resident islet macrophages in mice with and without the amyloidogenic form of human islet amyloid polypeptide (hIAPP). The role of islet amyloid in autoimmune diabetes and antigen presentation was assessed in hIAPP-expressing NOD mice and in antigen-presenting cells ex vivo.

MHC class II (MHCII) antigen presentation genes were strongly downregulated in islet macrophages during islet amyloid formation. NOD mice expressing an hIAPP transgene had delayed diabetes relative to littermate controls (median onset 30.3 vs 19.5 weeks, p=0.016). Likewise, physiological expression of hIAPP by genetic knockin also delayed diabetes in NOD mice relative to littermate controls (median onset 28.2 vs 18.0 weeks, p=0.049), 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 decreased antigen presentation in the pancreas. Consistent with this, incubation of dendritic cells with islet amyloid polypeptide (IAPP) aggregates decreased MHCII surface expression and diminished antigen-specific T cell activation through a phagocytosis-dependent mechanism.

Collectively, our data reveal a novel role for IAPP aggregates in decreasing MHCII antigen presentation and show that despite the well-established proinflammatory response of macrophages to IAPP aggregates, the uptake of IAPP aggregates during early amyloid formation also disrupts beta cell autoimmunity and delays diabetes in NOD mice.

The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-025-06622-0.