The intrinsic role of CD8α- dendritic cell subset in the initiation of effective humoral immunity

Abstract

Dendritic cells (DCs), the most potent antigen presenting cells, have been identified in 1973 by Ralph M. Steinman. DCs. DCs role as an immune initiator as well as regulator, have been intensively studied for their crucial function in regulating cellular and humoral immune responses. Efficiency of human vaccines is mostly dependent on the generation of proper humoral immunity, and recently T follicular helper (Tfh) cells have been identified as a true B cell helper, which significantly advanced our understanding of T cell-dependent B cell humoral immune responses. However, there are still little studies regarding the initial commitment of Tfh cells primed by DCs, particularly by the two major myeloid CD8α+ and CD8α- DC subsets. In this study, we present the undescribed intrinsic features and roles of the two DC subsets in the induction of Tfh cells and subsequent Tfh cell dependent humoral immune responses. We here demonstrate that the CD8α- DC subset critically roles in inducing antigen-specific Tfh cells by up-regulated expressions of Icosl and Ox40l via the non-canonical NF-κB signaling pathway. CD8α- DCs are able to induce functional Tfh cells regardless of an adjuvant type. Tfh cells initially primed by CD8α- DCs function as a true B cell helper that results in dramatically enhanced humoral immune responses against various human pathogenic antigens such as Yersinia pestis LcrV, HIV Gag, and Hepatitis B surface antigen. In addition, we showed that the localization of CD8α- DCs in the marginal zone (MZ) bridging channels is closely related to the induction of CXCR5+CCR7low Tfh cells. We also demonstrated that the major source of IL-6 for inducing Tfh cells is provided from the antigen specifically activated CD4+ T cells primed by CD8α- DCs, and those secreted by the DC subset seem have a minor role. Moreover, CD8α- DCs were superior in inducing functional Tfh cells over other antigen presenting cells majorly B cells. In contrast, CD8α+ DCs localized in the T cell enriched region are superior in inducing CXCR5lowCCR7high CD4+ T cells responsible for the generation of IFN-γ secreting Th1 cells. Taken together, this study reveals the undescribed intrinsic features and mechanistic role of the CD8α- DC subset in priming antigen-specific Tfh cell differentiation and thereby provides the potential of investigating CD8α- DCs to effectively evoke antigen-specific humoral immune responses through the improved therapeutic vaccines.