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Adaptation of innate immune cells to persistent viral infection


During chronic infections, sustained cell adaptation has been mostly studied in the adaptive immune compartment but much less is known on how innate immune cells adjust to a persistently infectious milieu. Particularly, dendritic cells (DCs), which are central players in immune responses, adapt during chronic infections. However, the underlying mechanisms remain largely unknown. Thus, to understand how short-lived innate cells adapt to lifelong persistent infections, we first studied plasmacytoid DCs (pDCs), which specialize in Type I Interferon (IFN-I) production and often become functionally exhausted in chronic settings. Using a murine chronic viral infection model of lymphocytic choriomeningitis virus (LCMV), we found that bone marrow pDC progenitors exhibited quantitative and qualitative defects and failed to generate functional pDCs ex vivo in an IFN-I-dependent manner. Exhausted pDC numbers were, however, maintained by peripheral self-renewal via sustained proliferation of CD4- pDC subsets that was induced by IFN-I receptor and Toll-like receptor 7 (TLR7) signaling in a cell-intrinsic manner. In contrast, functional impairment of exhausted pDCs was independent of IFN-I receptor signaling. We further studied mechanisms underlying adaptation of progenitors, that can give rise to conventional DCs (cDCs) as well as pDCs, by determining the transcriptional and chromatin landscapes of bone marrow DC progenitors from LCMV-infected mice and applying these datasets to Taiji algorithm to predict the activity of transcription factors (TFs). We found that, Glucocorticoid Modulatory Element Binding Protein 1 (Gmeb1), which was predicted to exhibit increased activity in progenitors during LCMV infection, suppressed pDC development in a glucocorticoid-dependent manner. Further studies revealed that glucocorticoid suppressed pDC development during LCMV infection. Gmeb1 also promoted development but suppressed maturation of cDC1s in a glucocorticoid-independent manner. Overall, our work provides a framework to understand how innate immune adaptation can be triggered and sustained during chronic viral infection. Moreover, by highlighting novel TF regulators of DC progenitors and their progeny, our work enhances our understanding of DC biology and unveils potential therapeutic targets to harness DCs.

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