Central and local adaptations sustain Type I Interferon exhaustion during chronic viral infection

Abstract During chronic infections, sustained cell adaptation via functional exhaustion 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. Thus, to understand how innate cells adapt to persistent infections, we studied plasmacytoid dendritic cells (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 we demonstrated that pDC IFN-I exhaustion is caused by concerted events at central (bone marrow) and local (spleen) compartments. On one hand, undifferentiated bone marrow pDC progenitors exhibited quantitative and qualitative defects and failed to generate functional pDCs ex vivo. Analysis of transcription and chromatin landscapes via RNA-seq and ATAC-seq revealed that IFN-I signaling pathway was enhanced in bone marrow pDC progenitors. Consistently, IFN-I receptor blockade restored the quantitative (albeit not the qualitative) defects of bone marrow pDC progenitors, which was accompanied by restoration of E2-2, a transcription factor critical for pDC development. On the other hand, splenic pDCs received sustained TLR7 signaling, which promoted their maturation but also rendered them unable to produce IFN-I upon ex vivo TLR re-stimulation or in vivo secondary infection. RNA-seq and ATAC-seq analysis in splenic pDCs revealed significant alterations in multiple pathways and transcriptional regulators that are currently being studied. Our work provides an anatomical, cellular and molecular framework to understand how innate immune exhaustion can be triggered and sustained during a chronic viral infection.