Patient iPSC-Derived Macrophages to Study Inborn Errors of the IFN-gamma Responsive Pathway

Interferon gamma (IFN-gamma) was shown to be a macrophage activating factor already in 1984. Consistently, inborn errors of IFN-gamma immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD). MSMD is characterized by genetic predisposition to disease caused by weakly virulent mycobacterial species. Paradoxically, macrophages from patients with MSMD were little tested. Here, we report a disease modeling platform for studying IFN-gamma related pathologies using macrophages derived from patient specific induced pluripotent stem cells (iPSCs). We used iPSCs from patients with autosomal recessive complete- and partial IFN-gammaR2 deficiency, partial IFN-gammaR1 deficiency and complete STAT1 deficiency. Macrophages from all patient iPSCs showed normal morphology and IFN-gamma-independent functionality like phagocytic uptake of bioparticles and internalization of cytokines. For the IFN-gamma-dependent functionalities, we observed that the deficiencies played out at various stages of the IFN-gamma pathway, with the complete IFN-gammaR2 and complete STAT1 deficient cells showing the most severe phenotypes, in terms of upregulation of surface markers and induction of downstream targets. Although iPSC-derived macrophages with partial IFN-gammaR1 and IFN-gammaR2 deficiency still showed residual induction of downstream targets, they did not reduce the mycobacterial growth when challenged with Bacillus Calmette-Guerin. Taken together, we report a disease modeling platform to study the role of macrophages in patients with inborn errors of IFN-gamma immunity.

• Haake, K.
• Neehus, A. L.
• Buchegger, T.
• Kuhnel, M. P.
• Blank, P.
• Philipp, F.
• Oleaga-Quintas, C.
• Schulz, A.
• Grimley, M.
• Goethe, R.
• Jonigk, D.
• Kalinke, U.
• Boisson-Dupuis, S.
• Casanova, J. L.
• Bustamante, J.
• Lachmann, N.