TY - JOUR
T1 - Regulatory T cells control toxicity in a humanized model of IL-2 therapy
AU - Li, Yan
AU - Strick-Marchand, Helene
AU - Lim, Ai Ing
AU - Ren, Jiazi
AU - Masse-Ranson, Guillemette
AU - Li, Dan
AU - Jouvion, Gregory
AU - Rogge, Lars
AU - Lucas, Sophie
AU - Li, Bin
AU - Di Santo, James P.
N1 - Funding Information:
The authors thank the Center for Translational Research and the Animalerie Centrale of Institut Pasteur for their collaboration. This work was supported in part by grants to J.P.D. from the Agence Nationale de la Recherche programme RPIB (Im_HIS), the Laboratoire d’Excellence REVIVE, European Commission Seventh Framework Programme n°305578 (PathCO), the Institut Pasteur, and INSERM. Y.L. received postdoctoral supported from the ANR and REVIVE.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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 immunotherapy 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 (Treg) cells after HDIL2 therapy further underscores the importance of Treg in the maintenance of immune tolerance. IL-2 toxicity is induced by selective depletion or inhibition of Treg 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.
AB - 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 immunotherapy 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 (Treg) cells after HDIL2 therapy further underscores the importance of Treg in the maintenance of immune tolerance. IL-2 toxicity is induced by selective depletion or inhibition of Treg 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.
UR - http://www.scopus.com/inward/record.url?scp=85035074401&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85035074401&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-01570-9
DO - 10.1038/s41467-017-01570-9
M3 - Article
C2 - 29176694
AN - SCOPUS:85035074401
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1762
ER -