Low-dose IL-2 reduces IL-21+ T cell frequency and induces anti-inflammatory gene expression in type 1 diabetes.

Abstract

Funder: China Scholarship CouncilDespite early clinical successes, the mechanisms of action of low-dose interleukin-2 (LD-IL-2) immunotherapy remain only partly understood. Here we examine the effects of interval administration of low-dose recombinant IL-2 (iLD-IL-2) in type 1 diabetes using high-resolution single-cell multiomics and flow cytometry on longitudinally-collected peripheral blood samples. Our results confirm that iLD-IL-2 selectively expands thymic-derived FOXP3+HELIOS+ regulatory T cells and CD56bright NK cells, and show that the treatment reduces the frequency of IL-21-producing CD4+ T cells and of two innate-like mucosal-associated invariant T and Vγ9Vδ2 CD8+ T cell subsets. The cellular changes induced by iLD-IL-2 associate with an anti-inflammatory gene expression signature, which remains detectable in all T and NK cell subsets analysed one month after treatment. These findings warrant investigations into the potential longer-term clinical benefits of iLD-IL-2 in immunotherapy.This work was supported by the Sir Jules Thorn Trust (13/JTA (OCT2013/DR/1044)), the JDRF (1-SRA-2019-657-A-N), and the NIHR Cambridge Biomedical Research Centre. The Diabetes and Inflammation Laboratory was supported by a strategic award from the Wellcome (107212/A/15/Z) and the JDRF (4-SRA-2017-473-A-A). JYZ was supported by the China Scholarship Council-University of Oxford Scholarship. The research was supported by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z with additional support from the NIHR Oxford BRC. The University of Cambridge has received salary support for ME through the National Health Service in the East of England through the Clinical Academic Reserve. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health