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

Abstract

Interferon γ (IFN-γ) was shown to be a macrophage activating factor already in 1984. Consistently, inborn errors of IFN-γ 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-γ 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-γR2 deficiency, partial IFN-γR1 deficiency and complete STAT1 deficiency. Macrophages from all patient iPSCs showed normal morphology and IFN-γ-independent functionality like phagocytic uptake of bioparticles and internalization of cytokines. For the IFN-γ-dependent functionalities, we observed that the deficiencies played out at various stages of the IFN-γ pathway, with the complete IFN-γR2 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-γR1 and IFN-γR2 deficiency still showed residual induction of downstream targets, they did not reduce the mycobacterial growth when challenged with Bacillus Calmette–Guérin. Taken together, we report a disease modeling platform to study the role of macrophages in patients with inborn errors of IFN-γ immunity.

Mechanistic and Translational Advances Using iPSC-Derived Blood Cells

“…iPSC-derived macrophages from immunodeficient patients with defective IFNγ responses, caused by deficiency in IFNγR1, IFNγR2, or STAT1, had normal morphology and displayed normal IFNγ-independent phagocytosis. However, these diseased cells were defective in containing weak mycobacterial infection in vitro, consistent with the related clinical phenotype [51]. These experiments provide proof-of-principal for iPSC-derived cells to be used as drug and treatment screening platforms, and for mechanistic studies into disorders related to IFNγ pathway deficiency.…”

Mechanistic and Translational Advances Using iPSC-Derived Blood Cells

“…iPSC-derived macrophages from immunodeficient patients with defective IFNg responses, caused by deficiency in IFNgR1, IFNgR2, or STAT1, had normal morphology and displayed normal IFNgindependent phagocytosis. However, these diseased cells were defective in containing weak mycobacterial infection in vitro, consistent with the related clinical phenotype [48]. These experiments provide proof-of-principal for iPSC-derived cells to be used as drug and treatment screening platforms, and for mechanistic studies into disorders related to IFNg pathway deficiency.…”

“…iPSC models can also provide cellular screening platforms for novel immunodeficiency syndrome treatments. For example, interferon g (IFNg) defects underlie genetic predisposition to mycobacterial infections [48]. IFNg is a key macrophage stimulating factor.…”

Macrophages as a Double-Edged Weapon: The Use of Macrophages in Cancer Immunotherapy and Understanding the Cross-Talk Between Macrophages and Cancer

“…Using iPSCs as a cornerstone to derive Mfs has allowed scientists to use these Mfs in a variety of different applications (Fig. 3) (Ackermann et al, 2018;Mucci et al, 2018;Haake et al, 2020). In our laboratory, we optimized a protocol to derive Mfs from iPSCs through the embryoid bodies (EBs) method in which iPSCs aggregate to form three-dimensional-like structures called EBs that have the three germ layers.…”

“…Serious adverse effects arising from systemic administration of cytotoxic drugs can cause severe clinical problems and the failure of therapeutic protocols, since these anticancer drugs can affect both cancerous and noncancerous cells (Xu and Wang, 2015). Interestingly, in clinical practice, immunotherapies relying on natural killer cells and T lymphocytes have shown significant benefits (Ruggeri et al, 2002;Kantoff et al, 2010;Ackermann et al, 2018;Haake et al, 2020). After surgery, radiation, and chemotherapy, immunotherapy (presented by immune cells, antibodies, and checkpoint inhibitors) is considered to be the fourth pillar of cancer treatment.…”