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

被引：0

作者：

Yan Li

Helene Strick-Marchand

Ai Ing Lim

Jiazi Ren

Guillemette Masse-Ranson

Gregory Dan Li

Lars Jouvion

Sophie Rogge

James P. Lucas

机构：

[1] Institut Pasteur,

[2] Innate Immunity Unit,undefined

[3] Immunology Department,undefined

[4] Inserm U1223,undefined

[5] Key Laboratory of Molecular Virology and Immunology,undefined

[6] CAS Center for Excellence in Molecular Cell Science,undefined

[7] Unit of Molecular Immunology,undefined

[8] Institut Pasteur of Shanghai,undefined

[9] Shanghai Institutes for Biological Sciences,undefined

[10] Chinese Academy of Sciences,undefined

[11] Shanghai Institute of Immunology,undefined

[12] Shanghai JiaoTong University School of Medicine,undefined

[13] Institut Pasteur,undefined

[14] Human Histopathology and Animal Models Unit,undefined

[15] Institut Pasteur,undefined

[16] Immunoregulation Unit,undefined

[17] Immunology Department,undefined

[18] de Duve Institute,undefined

[19] Université Catholique de Louvain,undefined

[20] and WELBIO,undefined

来源：

Nature Communications | / 8卷

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摘要：

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.

引用

共 86 条

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