CD169+ macrophages orchestrate plasmacytoid dendritic cell arrest and retention for optimal priming in the bone marrow of malaria-infected mice

Plasmacytoid dendritic cells (pDCs) are the most potent producer of type I interferon (IFN), but how pDC is primed in vivo is poorly defined. Using a mouse model of severe malaria, we have previously established that upon priming by CD169(+) macrophages (MPs), pDC initiates type I IFN-I secretion in the bone marrow (BM) of infected mice via cell-intrinsic TLR7 sensing and cell-extrinsic STING sensing. Herein we show that CD169(+) MP and TLR7 sensing are both required for pDC arrest during priming, suggesting CD169(+) MP are the source of TLR7 ligands. We establish that TLR7 sensing in pDC and chemotaxis are both required for pDC arrest and functional communication with CD169(+) MP in the BM. Lastly, we demonstrate that STING sensing in CD169(+) MP control pDC initiation of type I IFN production while also regulating pDC clustering and retention/egress from the BM. Collectively, these results link pDC acquisition of type I IFN-secreting capacity with changes in their motility, homing and interactions with CD169(+) MP during infection. Thus, targeting this cellular interaction may help modulate type I IFN to improve outcomes of microbial infections and autoimmune diseases.

Automated summary

This study reveals the critical roles of CD169(+) macrophages (MPs) and TLR7 sensing in initiating type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) in severe malaria. TLR7 sensing and chemotaxis are required for pDC arrest and functional communication with CD169(+) MPs, while STING sensing in CD169(+) MPs controls pDC initiation of type I IFN production and their clustering and egress from the bone marrow.