Regulatory T cells control toxicity in a humanized model of IL-2 therapy

Yan Li (1) , Helene Strick-Marchand (1) , Ai Ing Lim (1) , Jiazi Ren (2) , Guillemette Masse-Ranson (1) , Dan Li (2, 3) , Gregory Jouvion (4) , Lars Rogge (5) , Sophie Lucas (6) , Bin Li (2, 3) , James P. Di Santo (1)

1 Immunité Innée - Innate Immunity
2 LMVI - Key Laboratory of Molecular Virology & Immunology
3 University of Shanghai [Shanghai]
4 Histopathologie humaine et Modèles animaux
5 Immunorégulation
6 UCL - Université Catholique de Louvain = Catholic University of Louvain

While patient selection and clinical management have reduced high-dose IL-2 (HDIL2) immunotherapy toxicities, the immune mechanisms that underlie HDIL2-induced morbidity remain unclear. Here we show that dose-dependent morbidity and mortality of IL-2 immu-notherapy can be modeled in human immune system (HIS) mice. Depletion of human T cell subsets during the HDIL2 treatment reduces toxicity, pointing to the central function of T cells. Preferential expansion of effector T cells secondary to defective suppressive capacity of regulatory T (T reg) cells after HDIL2 therapy further underscores the importance of T reg in the maintenance of immune tolerance. IL-2 toxicity is induced by selective depletion or inhibition of T reg after LDIL2 therapy, and is ameliorated in HDIL2-treated HIS mice receiving the PIM-1 kinase inhibitor, Kaempferol. Modeling IL-2 pathophysiology in HIS mice offers a means to understand the functions of effector and regulatory T cells in immune-mediated toxicities associated with cancer immunotherapy.

Keywords: Translational immunology; Regulatory T cells; Interleukins; Immunosuppression

Domains: Life Sciences [q-bio]; Immunology

Yan Li, Helene Strick-Marchand, Ai Ing Lim, Jiazi Ren, Guillemette Masse-Ranson, et al.. Regulatory T cells control toxicity in a humanized model of IL-2 therapy. Nature Communications, 2017, 8 (1), pp.1762. ⟨10.1038/s41467-017-01570-9⟩. ⟨pasteur-01663992⟩