Mammalian cells have evolved multiple strategies to protect themselves against pathogens. In most cells, pathogen detection leads to production of interferons (IFNs), which act, in an autocrine and paracrine fashion, to induce hundreds of IFN stimulated genes (ISGs)1. These ISGs act collectively to inhibit virus infection and spread. Stem cell, however, are different than most cells. They do not produce IFNs2 and they respond weakly to IFNs3. It has been postulated that IFN signaling may be incompatible with stemness2,3. This raises the question: how do stem cells, which are essential for development and tissue repair, resist viral infection?
Researchers at Rockefeller University have been to understand how antiviral immunity might differ in stem cells versus differentiated cells. To address these fascinating but understudied questions, they analyzed gene expression in mammalian stem cells and cells at various stages of differentiation. They found that stem cells express a subset of genes previously classified as ISGs, but that expression was intrinsic, and not mediated by interferon. This intrinsic ISG expression varied in a cell-type-specific manner and many ISGs decreased upon stem cell differentiation at which time cells became interferon responsive, allowing induction of a broad spectrum of ISGs by interferon signaling.
To understand the role that these intrinsically expressed ISGs might play, they used a variety of viruses and stem cells. By knocking out several of these ISGs, they showed that intrinsically expressed ISGs are indeed important for protecting stem cells from viral infection both in vitro and in vivo. Without the expression of critical ISGs, stem cells were susceptible to infection and failed to regenerate tissue after viral infection. Similar observations were made from chimpanzee and mouse, suggesting a highly conserved antiviral mechanism across species4.
This study has solved a long-lasting mystery, the solution of which has implications for understanding of both stem cell biology and the evolution of the vertebrate pathogen defense response. It opens up a significant new research direction for the immunity field: to understand how intrinsic ISG expression and antiviral resistance are regulated in cells of fundamentally important for maintaining tissue and organ integrity. This work also provokes investigations to understand how pathogen encounters elicit intrinsic antiviral resistance in mammalian tissue stem cell-like cells, including memory T and B cells5, as well as innate immune cells formed during “trained immunity”6.
1 Schneider, W. M., Chevillotte, M. D. & Rice, C. M. Interferon-Stimulated Genes: A Complex Web of Host Defenses. Annu Rev Immunol. 32, 513-545 (2014).
2 Burke, D. C., Graham, C. F. & Lehman, J. M. Appearance of interferon inducibility and sensitivity during differentiation of murine teratocarcinoma cells in vitro. Cell 13, 243-248 (1978).
3 Hong, X.-X. & Carmichael, G. G. Innate Immunity in Pluripotent Human Cells: attenuated response to interferon-β. J. Biol. Chem. 288, 16196-16205 (2013).
4 Wu, X. et al. Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Cell 172, 1-16 (2018).
5 Wakim, L. M., Gupta, N., Mintern, J. D. & Villadangos, J. A. Enhanced survival of lung tissue-resident memory CD8+ T cells during infection with influenza virus due to selective expression of IFITM3. Nat Immunol 14, 238-245 (2013).
6 Netea, Mihai G., Quintin, J. & van der Meer, Jos W. M. Trained Immunity: A Memory for Innate Host Defense. Cell Host & Microbe 9, 355-361.