Critical Role for Skin-Derived Migratory DCs and Langerhans Cells in TFH and GC Responses after Intradermal Immunization

Abstract

Intradermal delivery of antigen represents a potent route of immunization that involves multiple blood- and skin-derived dendritic cell subpopulations endowed with specialized functions and dynamics in their ability to prime naïve CD4⁺ T cells in the draining lymph nodes. However, their individual contributions to the generation of CD4⁺ T follicular helper (T_FH) cells and germinal centers (GCs) remain to be understood. We found that intradermal immunization of mice with a particle-based vaccine induced robust T_FH and germinal center B-cell responses in skin draining lymph nodes, which were completely abrogated when skin cell emigration was prevented. However, in this later condition, both lymph node-resident and blood-derived inflammatory cells access the antigen in the draining lymph nodes but are not able to induce T_FH cell differentiation. Rather, only skin-derived dendritic cells up-regulated key genes related to T_FH cell development in the draining lymph nodes. Depletion of Langerhans cells partially abrogated T_FH and germinal center B-cell responses. Thus, after intradermal immunization, only skin-derived migratory dendritic cells, including Langerhans cells, permit the generation of T_FH cells and germinal centers. Identifying the relative contributions of tissue and lymphoid organ dendritic cell subsets in generating humoral immune responses is of great importance for the development of tailored vaccines.