Dendritic cells regulate innate cell trafficking and lymph node organization during inflammation

Abstract

Abstract Organization of immune cells within lymph nodes (LNs) is critical for effective host defense. During vaccination or infection, layers of innate cell activity in the outer periphery of the LN provide immediate protection, while antigen-presenting dendritic cells (DCs) migrate into the T cell zone (TZ), located deeper in the LN, to initiate later-stage adaptive responses. Using mouse models of vaccination and infection, we now find that DC activation and repositioning into the TZ is tightly associated with localized recruitment of multiple innate effector cells, including neutrophils, monocytes, and NK cells, which also rapidly infiltrate the TZ. As activated DCs migrated towards the TZ, they passed by the high endothelial venules (HEVs), where they expressed multiple inflammatory chemokines and high levels of the integrin ligand, ICAM-1, generating a chemokine- and adhesion molecule-rich matrix ripe for innate cell migration. Depletion of DCs, or conditional ablation of ICAM-1, significantly impaired innate cell trafficking into LNs, and cells which did enter remained largely trapped near the HEVs and were less able to infiltrate the TZ. While essential for innate defense, neutrophil influx also led to large-scale disruption of the TZ and impaired early T cell activation. However, over time this was controlled by DCs and DC-recruited monocytes, which efferocytosed the infiltrating neutrophils and cleared the TZ to allow productive adaptive responses to occur. Thus, in addition to their classical roles in antigen presentation, DCs orchestrate innate cell recruitment and activation across the entire LN, to promote both effective innate defense as well as rapid restoration of LN architecture for the generation of adaptive immunity. Supported by grant from NIH (1F31AI161316-01).