Impaired IFNg-signaling and mycobacterial clearance in IFNgR1-deficient human iPSC-derived macrophages

Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of interferon gamma (IFNg) immunity and is characterized by severe infections by weakly virulent mycobacteria. Although IFNg 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 IFNgR1 deficiency and received bone-marrow transplantation. Loss of IFNgR1 expression had no influence on the macrophage differentiation potential of patient-specific iPSCs. In contrast, lack of IFNgR1 in iMSMD-cohet macrophages abolished IFNg-dependent phosphorylation of STAT1 and induction of IFNg-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 IFNg signaling in macrophages.