Beta cell-immune cell crosstalk in T1D

β-cell stress can influence immune cell activity and function in the pancreas through a multitude of mechanisms. For example, ER stress interferes with major histocompatibility complex (MHC) class I protein surface expression and peptide presentation, thus differentially regulating expression of ER- versus cytosol-derived peptide. ER stress can lead to formation of neoantigens that can trigger autoimmunity. During cellular stress, ER chaperones that are typically retained in the ER can be translocated to the cell surface and act as an “eat me” signal. These proteins can also be released from chronically stressed and dying cells and activate the immune system. Moreover, in addition to the immune effectors, β-cells themselves secrete chemokines and contribute to the early steps of immune cell recruitment, activation, and inflammation.

We recently showed that the deletion of the unfolded protein response (UPR) genes Atf6α or Ire1α in β-cells of non-obese diabetic (NOD) mice prior to initiation of islet inflammation (insulitis) generates a p21-driven early senescence phenotype and alters the β-cell secretome that significantly enhances the leukemia inhibitory factor (LIF)-mediated recruitment of M2 macrophages to pancreatic islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause the resolution of islet inflammation, the removal of terminally senesced β-cells, reduction of β-cell apoptosis, and protection against T1D (Lee et al., Cell Metab 2023).

Our knowledge on the interaction of the senescent β-cell and immune cells in T1D is limited. Several important questions remain unanswered. For example: Which immune cell types do play a role in senescent cell immunesurveillance? What are the molecular signatures of immune subtypes involved in senescent cell clearance? Are there sex-dependent differences in UPR-deficient β-cells’ interaction with islet infiltrated/resident immune cells? Answering these questions holds great importance for targeting immunosurveillance in the clinic setting.