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

• Published in: Nature communications Vol. 13; no. 1; pp. 7324 - 17
• Main Authors: Zhang, Jia-Yuan, Hamey, Fiona, Trzupek, Dominik, Mickunas, Marius, Lee, Mercede, Godfrey, Leila, Yang, Jennie H. M., Pekalski, Marcin L., Kennet, Jane, Waldron-Lynch, Frank, Evans, Mark L., Tree, Timothy I. M., Wicker, Linda S., Todd, John A., Ferreira, Ricardo C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.11.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 38/39; 45; 45/91; 49/31; 631/1647/514/1949; 631/250/249/1313/1418; 692/308/575; 692/699/249/2510; 82/1; 82/80; Anti-Inflammatory Agents; CD4 antigen; CD8 antigen; Cytokines; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - genetics; Dosage; Flow cytometry; Foxp3 protein; Gene Expression; Health services; Humanities and Social Sciences; Humans; Immune system; Immunoregulation; Immunotherapy; Inflammatory diseases; Interleukin 2; Interleukin 21; Interleukin-2 - genetics; Lymphocytes; Lymphocytes T; multidisciplinary; Natural killer cells; Peripheral blood; Science; Science (multidisciplinary); T-Lymphocytes - immunology; Thymus
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34162-3

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 γ9 V 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. Low-dose interleukin-2 is showing promise in the treatment of several autoimmune inflammatory diseases. Here authors map the trajectory of cellular and transcriptional changes in type 1 diabetes patients receiving an interval dosing interleukin-2 regimen, which shows an anti-inflammatory gene expression signature shared by all immune cell types analysed, persisting for at least a month after ending treatment.