Impaired IFNγ-Signaling and Mycobacterial Clearance in IFNγR1-Deficient Human iPSC-Derived Macrophages.

Abstract

Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of interferon gamma (IFNγ) immunity and is characterized by severe infections by weakly virulent mycobacteria. Although IFNγ is the macrophage-activating factor, macrophages from these patients have never been studied. We demonstrate the generation of heterozygous and compound heterozygous (iMSMD-cohet) induced pluripotent stem cells (iPSCs) from a single chimeric patient, who suffered from complete autosomal recessive IFNγR1 deficiency and received bone-marrow transplantation. Loss of IFNγR1 expression had no influence on the macrophage differentiation potential of patient-specific iPSCs. In contrast, lack of IFNγR1 in iMSMD-cohet macrophages abolished IFNγ-dependent phosphorylation of STAT1 and induction of IFNγ-downstream targets such as IRF-1, SOCS-3, and IDO. As a consequence, iMSMD-cohet macrophages show impaired upregulation of HLA-DR and reduced intracellular killing of Bacillus Calmette-Guérin. We provide a disease-modeling platform that might be suited to investigate novel treatment options for MSMD and to gain insights into IFNγ signaling in macrophages.

• Authors: Anna-Lena Neehus, Jenny Lam, Kathrin Haake, Sylvia Merkert, Nico Schmidt, Adele Mucci, Mania Ackermann, Madline Schubert, Christine Happle, Mark Philipp Kühnel, Patrick Blank, Friederike Philipp, Ralph Goethe, Danny Jonigk, Ulrich Martin, Ulrich Kalinke, Ulrich Baumann, Axel Schambach, Joachim Roesler, Nico Lachmann
• Journal: Stem cell reports (Stem Cell Reports) Vol. 10 Issue 1 Pg. 7-16 (01 09 2018) ISSN: 2213-6711 [Electronic] United States
• PMID: 29249666 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• IFNG protein, human
• Receptors, Interferon
• Interferon-gamma

Topics

• Genetic Predisposition to Disease
• Humans
• Induced Pluripotent Stem Cells (immunology, microbiology, pathology)
• Interferon-gamma (genetics, immunology)
• Macrophages (immunology, microbiology, pathology)
• Mycobacterium bovis (immunology)
• Receptors, Interferon (deficiency, immunology)
• Signal Transduction (genetics, immunology)
• Interferon gamma Receptor