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

Despite 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 CD56^bright 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 V_γ9V_δ2 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.