Using an assay to identify DCs that rapidly and preferentially phagocytosed 2ⲙM macroparticles (MP; bacteria-sized), Deak et al. identified a small subpopulation of CD11b+SIRPα+ cDC2-related DCs, “first responders” (FR). Coating the MP with TLR agonists led to rapid release of TNFα (stored in vesicles) and upregulation of IFNβ production from these FRs. FR stimulation was transient (over hours) and led to production of other mediators that stimulated secondary DC activity. Liposomes targeting DAP12 and PRG2, which were relatively uniquely co-expressed in FRs, demonstrated promise for in vivo delivery and enhancement of adaptive immunity.
Contributed by Ed Fritsch
ABSTRACT: Dendritic cell (DC) activation via pathogen-associated molecular patterns (PAMPs) is critical for antigen presentation and development of adaptive immune responses, but the stochastic distribution of DC responses to PAMP signaling, especially during the initial stages of immune activation, is poorly understood. In this study, we isolate a unique DC subpopulation via preferential phagocytosis of microparticles (MPs) and characterize this subpopulation of "first responders" (FRs). We present results that show these cells (1) can be isolated and studied via both increased accumulation of the micron-sized particles and combinations of cell surface markers, (2) show increased responses to PAMPs, (3) facilitate adaptive immune responses by providing the initial paracrine signaling, and (4) can be selectively targeted by vaccines to modulate both antibody and T cell responses in vivo. This study presents insights into a temporally controlled, distinctive cell population that influences downstream immune responses. Furthermore, it demonstrates potential for improving vaccine designs via FR targeting.