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

Abstract

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 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.

Genetic evidence for efficacy of targeting IL-2, IL-6, and TYK2 signaling in prevention of type 1 diabetes: A Mendelian randomization study

“…These characteristics of immune system are achieved by the differences in affinity to IL-2 between the high-affinity heterotrimeric receptor in regulatory T-cells, which consists of α-, β-, and γ-chains encoded by IL2RA, IL2RB , and IL2RG genes, respectively, and intermediate-affinity heterodimeric receptor (consisting of only β- and γ-chains) in other cells that express only IL2RB and IL2RG 16 . Thus, our finding supports the rationale of prevention trials of type 1 diabetes with low dose IL-2 17 , which expands the population of regulatory T-cells without excessively amplifying effector T-cell or NK cell populations 18 .…”

Assessing the Effectiveness of Interleukin-2 Therapy in Experimental Type 1 Diabetes

“…Finding an optimal IL-2 dose has been the focus of many studies (Dutcher et Zhang et al, 2022). Indeed, high dose IL-2 was found to increase IFN-γ production in NK cells and CD8 + T cells, and to be lethal to NOD mice (Baeyens et al, 2013).…”

SARS-CoV-2 infection induces a long-lived pro-inflammatory transcriptional profile

“…Each sample contained five major cell types — CD4 + regulatory T cells (Treg), CD4 + conventional T cells (Tconv), CD8 + T cells, CD56 bright NK cells and CD56 dim NK cells — isolated by fluorescence-activated cell sorting (FACS) from peripheral blood mononuclear cells (PBMCs) and labelled with antibody-derived tags. Only day 0 and day 55 samples were analysed in the current study, with one sample (day 55 sample from participant P8) excluded due to quality control reasons previously described [ 4 ]. The DILfrequency dataset also contained cells stimulated with phorbol myristate acetate (PMA)/ionomycin, which were excluded from the current study.…”

“…Recently, we have employed targeted single-cell multiomics to characterise the immune response to low-dose IL-2 immunotherapy in newly diagnosed type 1 diabetes patients from the DILfrequency study [ 3 ]. We identified a prolonged anti-inflammatory gene expression signature induced by low-dose IL-2 treatment (IL2-AIS) in all the T and NK cell subsets studied [ 4 ]. The transcriptional changes associated with the IL2-AIS detected in samples taken 28 days after the last IL-2 injection were not anticipated since Treg frequencies had returned to baseline by this timepoint.…”