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

Jia-Yuan Zhang, Fiona Hamey, Dominik Trzupek, Marius Mickunas, Mercede Lee, Leila Godfrey, Jennie H. M. Yang, Marcin L. Pekalski, Jane Kennet, Frank Waldron-Lynch, Mark L. Evans, Timothy I. M. Tree, Linda S. Wicker, John A. Todd () and Ricardo C. Ferreira ()
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Jia-Yuan Zhang: University of Oxford
Fiona Hamey: University of Oxford
Dominik Trzupek: University of Oxford
Marius Mickunas: School of Immunology and Microbial Sciences
Mercede Lee: University of Oxford
Leila Godfrey: University of Oxford
Jennie H. M. Yang: School of Immunology and Microbial Sciences
Marcin L. Pekalski: University of Oxford
Jane Kennet: University of Cambridge
Frank Waldron-Lynch: Vertex Cell & Gene Therapies
Mark L. Evans: University of Cambridge
Timothy I. M. Tree: School of Immunology and Microbial Sciences
Linda S. Wicker: University of Oxford
John A. Todd: University of Oxford
Ricardo C. Ferreira: University of Oxford

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34162-3

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