DC subsets are functionally specialized to induce GC-dependent or -independent humoral immune responses

Abstract

Abstract Our knowledge of humoral immunity mainly comes from experimental vaccine models that use high antigen doses injected into the periphery in combination with adjuvants. This allows extended exposure to antigen/adjuvant by all of the immune cells. Thus, the contribution of a specific immune cell to humoral immune responses cannot be easily determined. To better understand the roles of different dendritic cell (DC) subsets in regulating humoral immunity, we developed a system to limit antigen availability and presentation to certain skin DC subsets. We found that antigen delivery without adjuvants to Langerhans cells (LCs) through the c-type lectin Langerin led to higher antibody titers and affinity, involved GC formation and was dependent on antigen dose and CD40 and IL-10 signaling, unlike the response initiated by CD103+DCs that produced lower antibody titers in a GC-independent manner and was characterized by long-lived PC formation. Interestingly, co-delivery of IFNa or poly-IC enabled CD103+DCs to drive GC-dependent humoral immune responses. Surprisingly, when both DC subsets had the antigen, the humoral immune response was like the one induced by the CD103+DCs alone but was dominated by memory/PB formation. Consistent with the B cell responses, the LC-induced Tfh cells were CD69+ S1PR1low and efficiently migrated to the B cell area, while the ones induced by the CD103+DCs were CD69− S1PR1high and localized mainly to the T cell zone. CD69 expression on Th cells inversely correlated with the antigen presentation capacity of the DCs. LCs, unlike CD103+DCs, migrated into the B cell area including B cell follicles and GCs. Thus, pre-programmed DC-intrinsic features allow DC subsets to induce distinct B cell responses.