Engineering synthetic vaccines using cues from natural immunity - PubMed (original) (raw)

Figure 1. Pathogen sensing by the immune system and immune context during the priming of an adaptive immune response

DCs are a central interpreter in distinguishing between foreign and self-antigens in the context of microenvironmental cues, and play a major role (along with other innate immune cells) in determining the outcome of antigen recognition by T- and B-cells. A, At steady state, immature DCs (iDCs) throughout the periphery constantly sample their environment and encounter 1) immunogenic signals from infected or immunized, dying cells, accompanied by triggering of danger sensors (TLRs, CLRs, NLRs, RLRs, SRs) or 2) tolerogenic signals from dying self-cells or cellular debris generated by homeostatic turnover; these produce a continuous spectrum of output responses ranging from strong induction of effector phase immunity to strong induction of tolerance, with the exact outcome determined by the integration of inputs by the DC. Pathogen detection occurs via a conserved suite of danger sensors relies on detection of “danger signals,” microbe-associated products with distinct molecular motifs. Different sensors are present in endosomes (TLRs, SRs), the cytosol (RLRs, NLRs), the ER (SRs) and the plasma membrane (TLRs, CLRs). Each danger sensor recognizes a different motif that is present in a class of microbes but absent from host tissues. In response to these “danger” or tolerizing signals, DCs (and other innate cells) create the immunological context for antigen recognition by secreting cytokines, expressing diverse adhesive, costimulatory or regulatory receptors that provide cues to responding lymphocytes. B, In immunogenic contexts, responding B-cells can subsequently enter germinal centers to undergo somatic hypermutation, become short-lived plasmablasts, or differentiate into long-lived memory B-cells or plasma cells. T-cells can differentiate into effector cells or memory cells with distinct homing and functional capacities; effector cells can have diverse functions (Th1, Th2, Th17, etc.) depending on the context set by DCs. Notably, regulatory feedback loops are engaged even in highly inflammatory contexts, as part of the natural control system regulating immunity, and primed effector cells can be driven to anergic/exhausted states similar to tolerance at later stages of an immune response. C, Peripheral tolerance is maintained by a distinct set of signals, e.g., apoptotic cells that die during homeostatic turnover contain ligands that activate the plasma membrane-expressed Tyro-3, Axl, and Mer (TAM) family receptor tyrosine kinases, inhibiting DC activation and maturation. Many additional APCs also participate in tolerogenic signaling. In tolerogenic contexts, T-cells are driven into several different states of non-responsiveness (anergy, exhaustion, deletion, or regulatory fates) that prevent effector responses against self or harmless environmental antigens.