Dendritic cells regulate innate cell trafficking into lymph nodes during inflammation

Abstract

Abstract Dendritic cells (DCs) have well-established roles in antigen presentation, and we recently showed that within several hours of immunization, lymph node (LN) resident DCs undergo activation and reposition into the T cell zone (TZ) to drive early T cell activation. Concurrently, monocytes are also recruited into LNs via high endothelial venules (HEVs) and cooperate with DCs to enhance the generation of adaptive responses. However, the mechanisms driving monocyte recruitment are unknown. Here, we used mouse models of immunization, quantitative imaging, and RNA sequencing to study early innate responses in draining LNs. We find that during inflammation, monocytes as well as neutrophils rapidly infiltrated the LN parenchyma and the TZ, with the timing of cell influx being concordant with that of DC activation and repositioning. As the DCs migrated towards the TZ, they passed through regions highly enriched in HEVs. DCs also expressed multiple inflammatory chemokines involved in monocyte and neutrophil trafficking, as well as high levels of the integrin ligand, ICAM-1, thus generating chemokine- and adhesion molecule-rich perivascular microenvironments. Depletion of DCs or ablation of ICAM-1 in DCs significantly decreased innate cell trafficking into LNs, with the recruited cells being largely trapped near HEVs and less able to infiltrate the TZ. Disruption of DC repositioning with conditional CCR7 ablation also resulted in the mislocalization of neutrophils and monocytes within the LNs. Thus, in addition to their classical roles as antigen presenting cells, during inflammation, DCs facilitate the recruitment of several innate cell types into LNs and guide them into the TZ to promote the generation of functional immune responses. Supported by NIH grants R01AI134713, R21AI142667, T32GM007270 (J.H.), and F31AI161316 (J.H.).