CD8α^- Dendritic Cells Induce Antigen-Specific T Follicular Helper Cells Generating Efficient Humoral Immune Responses

Recent studies on T follicular helper (Tfh) cells have significantly advanced our understanding of T cell-dependent B cell responses. However, little is known about the early stage of Tfh cell commitment by dendritic cells (DCs), particularly by the conventional CD8α⁺ and CD8α^- DC subsets. We show that CD8α^- DCs localized at the interfollicular zone play a pivotal role in the induction of antigen-specific Tfh cells by upregulating the expression of Icosl and Ox40l through the non-canonical NF-κB signaling pathway. Tfh cells induced by CD8α^- DCs function as true B cell helpers, resulting in significantly increased humoral immune responses against various human pathogenic antigens, including Yersinia pestis LcrV, HIV Gag, and hepatitis B surface antigen. Our findings uncover a mechanistic role of CD8α^- DCs in the initiation of Tfh cell differentiation and thereby provide a rationale for investigating CD8α^- DCs in enhancing antigen-specific humoral immune responses for improving vaccines and therapeutics. Shin et al. demonstrate that the CD8α^- DC subset efficiently induces functional antigen-specific Tfh cells to generate both high-quality and high-quantity humoral immune responses. Furthermore, they describe a critical role of non-canonical NF-κB-induced ICOSL and OX40L on CD8α^- DCs in Tfh cell differentiation.