Abstract Human epidermal and mucosal Langerhans cells (LCs) express the C-type lectin receptor langerin that functions as a pattern recognition receptor. LCs are among the first immune cells to interact with HIV-1 during sexual transmission. In this study, we demonstrate that langerin not only functions as a pattern recognition receptor but also as an adhesion receptor mediating clustering between LCs and dendritic cells (DCs). Langerin recognized hyaluronic acid on DCs and removal of these carbohydrate structures partially abrogated LC–DC clustering. Because LCs did not cross-present HIV-1–derived Ags to CD8+ T cells in a cross-presentation model, we investigated whether LCs were able to transfer Ags to DCs. LC–DC clustering led to maturation of DCs and facilitated Ag transfer of HIV-1 to DCs, which subsequently induced activation of CD8+ cells. The rapid transfer of Ags to DCs, in contrast to productive infection of LCs, suggests that this might be an important mechanism for induction of anti–HIV-1 CD8+ T cells. Induction of the enzyme hyaluronidase-2 by DC maturation allowed degradation of hyaluronic acid and abrogated LC–DC interactions. Thus, we have identified an important function of langerin in mediating LC–DC clustering, which allows Ag transfer to induce CTL responses to HIV-1. Furthermore, we showed this interaction is mediated by hyaluronidase-2 upregulation after DC maturation. These data underscore the importance of LCs and DCs in orchestrating adaptive immunity to HIV-1. Novel strategies might be developed to harness this mechanism for vaccination.