Pancreatic Islet Cells Response to IFNγ Relies on Their Spatial Location within an Islet

Type 1 diabetes (T1D) is an auto-immune disease characterized by the progressive destruction of insulin-producing pancreatic beta cells. While beta cells are the target of the immune attack, the other islet endocrine cells, namely the alpha and delta cells, can also be affected by the inflammatory milieu. Here, using a flow cytometry-based strategy, we compared the impact of IFN gamma, one of the main cytokines involved in T1D, on the three endocrine cell subsets isolated from C57BL/6 mouse islets. RNA-seq analyses revealed that alpha and delta cells exposed in vitro to IFN gamma display a transcriptomic profile very similar to that of beta cells, with an increased expression of inflammation key genes such as MHC class I molecules, the CXCL10 chemokine and the programmed death-ligand 1 (PD-L1), three hallmarks of IFN gamma signaling. Interestingly, at low IFN gamma concentration, we observed two beta cell populations (responders and non-responders) based on PD-L1 protein expression. Our data indicate that this differential sensitivity relies on the location of the cells within the islet rather than on the existence of two different beta cells subsets. The same findings were corroborated by the in vivo analysis of pancreatic islets from the non-obese diabetic mouse model of T1D, showing more intense PD-L1 staining on endocrine cells close to immune infiltrate. Collectively, our work demonstrates that alpha and delta cells are as sensitive as beta cells to IFN gamma, and suggests a gradual diffusion of the cytokine into an islet. These observations provide novel insights into the in situ inflammatory processes occurring in T1D progression.

Automated summary

Type 1 diabetes (T1D) is an autoimmune disease characterized by destruction of insulin-producing pancreatic beta cells. This study demonstrates that alpha and delta cells, in addition to beta cells, are also sensitive to the cytokine IFN gamma. The differential sensitivity of beta cells to IFN gamma is dependent on cell location within the islet, rather than the presence of distinct beta cell subsets. These findings provide new insights into the inflammatory processes occurring in T1D progression.