Skin-resident dendritic cells (DC) play a crucial role in initiation of adaptive immune responses against cutaneous pathogens as well as in the maintenance of peripheral tolerance. However, the immune response induced by skin DC against foreign antigen in the absence of adjuvants has not been addressed. Here we report that, using anti-huLangerin/ muLangerin antibodies, we could specifically target antigens to LC or CD103+ dermal DC. Targeting foreign peptide 2W1S by either LC or CD103+ dDC was sufficient for expansion of naïve CD4+ T cells and induction of T follicular helper cell (Tfh) differentiation. The expansion of Tfh specific to foreign peptide was accompanied by activation and expansion of antigen-specific B cells and the development of a robust antibody response that provided systemic protection against influenza infection. Using huLang LCΔMHC-II mice, we showed that CD4+ T cell proliferation was intact despite the MHC II deficiency on LC after targeting antigen to LC. We found that antigen targeted LC handed over antigen to CD11b+ dDC and DN dDC. We also showed MHC II deficient LC acquired MHC II in the lymph node through cross-dressing. This study reveals a major unappreciated function of skin DC in humoral response, and the communication between DC subsets, which provides insight into DC-targeted vaccine design.