[en] Interleukin-2 (IL-2) holds promise for the treatment of cancer and autoimmune diseases, but its high-dose usage is associated with systemic immunotoxicity. Differential IL-2 receptor (IL-2R) regulation might impact function of cells upon IL-2 stimulation, possibly inducing cellular changes similar to patients with hypomorphic IL2RB mutations, presenting with multiorgan autoimmunity. Here, we show that sustained high-dose IL-2 stimulation of human lymphocytes drastically reduces IL-2Rβ surface expression especially on T cells, resulting in impaired IL-2R signaling which correlates with high IL-2Rα baseline expression. IL-2R signaling in NK cells is maintained. CD4+ T cells, especially regulatory T cells are more broadly affected than CD8+ T cells, consistent with lineage-specific differences in IL-2 responsiveness. Given the resemblance of cellular characteristics of high-dose IL-2-stimulated cells and cells from patients with IL-2Rβ defects, impact of continuous IL-2 stimulation on IL-2R signaling should be considered in the onset of clinical adverse events during IL-2 therapy.
Disciplines :
Immunology & infectious disease
Author, co-author :
Sommer, Charline; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
Jacob, Sophie; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
Bargmann, Tonia; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
SHOAIB, Muhammad ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Clinical and Translational Informatics
ALSHAIKHDEEB, Basel M.M. ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Clinical and Translational Informatics
SATAGOPAM, Venkata ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Clinical and Translational Informatics
Dehmel, Susann; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
Neuhaus, Vanessa; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
Braun, Armin; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany, Institute of Immunology, Hannover Medical School, Hannover, Germany
Sewald, Katherina; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany. Electronic address: katherina.sewald@item.fraunhofer.de
External co-authors :
yes
Language :
English
Title :
Bridging therapy-induced phenotypes and genetic immune dysregulation to study interleukin-2-induced immunotoxicology.
H2020 - 853988 - imSAVAR - Immune Safety Avatar: nonclinical mimicking of the immune system effects of immunomodulatory therapies
Name of the research project :
Immune Safety Avatar (imSAVAR)
Funders :
Innovative Medicines Initiative European Commission European Federation of Pharmaceutical Industries and Associations Juvenile Diabetes Research Foundation United States of America European Union
Funding number :
853988
Funding text :
This project is part of the imSAVAR project (https://imsavar.eu/) which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 853988 (principial funding recipients: AB, KS; PhD thesis of CS partly funded). The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and JDRF INTERNATIONAL.
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