Induction of protective humoral immune responses at steady-state.

The specific roles of dendritic cell (DC) subsets in regulating antibody responses are essentially unknown. Here, we used a steady-state targeting system to determine the contribution of two skin dendritic cell (DC) subsets in the induction and regulation of humoral immunity to a foreign antigen. We found that Langerhans cells (LCs) targeting, but not cDC1s, through the same receptor (Langerin) led to a robust and protective humoral immune response. LCs, unlike cDC1s, supported the formation of germinal center T follicular helper cells (GC-Tfh), and then, likely licensed by these T cells, some of the LCs migrated to the B cell area to initiate B cell responses. Furthermore, we found that the cDC1s prevented the LCs from inducing GC-Tfh cells and humoral immune responses. cDC1s likely achieved this through their superior T cell activation capacity. Overall, these data suggest that an adjuvant-free vaccine could be a viable option to promote protective immune responses if targeted to a specific DC subset. Our findings also revealed that contrary to the accepted danger model, specific DC subsets could support adaptive immune responses without inflammation. Here, we showed that type I interferon and IL-6 signaling pathways, significant contributors to Tfh cell differentiation in inflammatory settings, played no role in LC-induced adaptive immune responses at steady-state. However, the membrane-bound co-stimulatory molecule ICOS/ICOSL regulates germinal center formation. Therefore, these data suggest that adaptive immune responses against foreign antigens in the absence of inflammation are generated through a mechanism that likely does not involve inflammatory cytokines. Identifying DC factors promoting humoral immune responses in a non-inflammatory environment could help understand how antibody-based autoimmune diseases develop and devise more efficient immuno-therapeutics.