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Interleukin-2 immunotherapy reveals human regulatory T cell subsets with distinct functional and tissue-homing

Miro E Raeber1, Dominic P Caspar2, Yves Zurbuchen2

  • 1Department of Immunology, University Hospital Zurich, 8091 Zurich, Switzerland; Faculty of Medicine, University of Zurich, 8032 Zurich, Switzerland; Center of Human Immunology, University of Zurich, 8006 Zurich, Switzerland.

Immunity
|August 13, 2024
PubMed

Due to its stimulatory potential for immunomodulatory CD4+ regulatory T (Treg) cells, low-dose interleukin-2 (IL-2) immunotherapy has gained considerable attention for the treatment of autoimmune diseases. In this investigator-initiated single-arm non-placebo-controlled phase-2 clinical trial of low-dose IL-2 immunotherapy in systemic lupus erythematosus (SLE) patients, we generated a comprehensive atlas of in vivo human immune responses to low-dose IL-2. We performed an in-depth study of circulating and cutaneous immune cells by imaging mass cytometry, high-parameter flow cytometry, transcriptomics, and targeted serum proteomics. Low-dose IL-2 stimulated various circulating immune cells, including Treg cells with a skin-homing phenotype that appeared in the skin of SLE patients in close interaction with endothelial cells. Analysis of surface proteins and transcriptomes revealed different IL-2-driven Treg cell activation programs, including gut-homing CD38+, skin-homing HLA-DR+, and highly proliferative inflammation-homing CD38+ HLA-DR+ Treg cells. Collectively, these data define the distinct human Treg cell subsets that are responsive to IL-2 immunotherapy.

Keywords:
IL-2SLETregclinical trialepigenomicsimaging mass cytometryinterleukin-2lupusregulatory T celltranscriptomics

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