Skin dendritic cells induce follicular helper T cells and protective humoral immune responses

Background The contribution of individual subsets of dendritic cells (DCs) to generation of adaptive immunity is central to understanding immune homeostasis and protective immune responses. Objective We sought to define functions for steady-state skin DCs. Methods We present an approach in which we restrict antigen presentation to individual DC subsets in the skin and monitor the effects on endogenous antigen-specific CD4⁺ T- and B-cell responses. Results Presentation of foreign antigen by Langerhans cells (LC) in the absence of exogenous adjuvant led to a large expansion of T follicular helper (T_FH) cells. This was accompanied by B-cell activation, germinal center formation, and protective antibody responses against influenza. The expansion of T_FH cells and antibody responses could be elicited by both systemic and topical skin immunization. T_FH cell induction was not restricted to LCs and occurred in response to antigen presentation by CD103⁺ dermal DCs. CD103⁺ DCs, despite inducing similar T_FH responses as LCs, were less efficient in induction of germinal center B cells and humoral immune responses. We also found that skin DCs are sufficient to expand CXCR5⁺ T_FH cells through an IL-6– and IFN-α/β receptor–independent mechanism, but B cells were required for sustained Bcl-6⁺ expression. Conclusions These data demonstrate that a major unappreciated function of skin DCs is their promotion of T_FH cells and humoral immune responses that potentially represent an efficient approach for vaccination.