DCs are the most potent APCs for inducing activation and differentiation of naïve T cells and for initiating primary and secondary immune responses. Immune complexes influence

these processes by affecting DCs in several ways: engagement of activating FcγRs on immature DCs leads to (i) the activation and maturation of DCs 26, 27, (ii) expression of the costimulator BAY 73-4506 purchase TL1A on DCs, which subsequently acts on activated T and NK cells 28, and (iii) an increased capability of DCs to cross-present complexed Ag to CD8+ T-cells 26, 27, 29. Collectively, these effects result in an augmented capacity of DCs to stimulate and modulate T-cell responses. On the contrary, engagement of the inhibitory receptor FcγRIIB has an opposing effect and downmodulates the ability of DCs to induce T-cell responses 27, 29, 30. Lumacaftor manufacturer Since specific Abs are generated after induction of

primary T-cell responses, their ability to influence T-cell responses is mainly confined to secondary responses. Indeed, secondary T-helper (Th) cell responses are significantly reduced in FcRγ−/− or B-cell-deficient mice and Th cells from these mice show decreased proliferation upon restimulation and secrete lower amounts of IL-2 and IFN-γ 31, whereas primary T-cell responses are normal. These results suggest that in secondary immune responses pre-existing Abs complex Ags and DCs interact with these immune complexes via their FcγR. This results in increased Ag presentation and activation of the APC, which then stimulates recall T-cell responses more efficiently. The presence of complexed Ag not only augments T-cell responses but also influences the type of response that is generated. How complexed Ag influences the nature of a T-cell response is illustrated

by the different Th-cell phenotypes generated when naïve CD4+ T cells are primed in vitro by APCs that received soluble or Ig-complexed Ag. When soluble Ag is added to macrophages or DCs, they produce IL-12 and the resulting Th-cell response is dominated by IFN-γ; however, when the APCs receive Ig-complexed Ag, IL-12 levels are reduced and IL-10 is produced instead, which favors the induction of Th2 responses 32, 33. Similarly, Calpain sheep red blood cells (SRBCs) coated at moderate densities with IgG are efficiently phagocytosed by LPS-stimulated murine macrophages and induce IL-12 production. At higher densities of IgG on SRBCs and as a result of excessive FcγR cross-linking, the production of IL-12 is diminished and high levels of anti-inflammatory IL-10 are released 34. The ability of immune complexes to shift immune responses toward a Th2 phenotype has also been confirmed in vivo by engaging FcγRIII on DCs 35 or by analyzing allergic responses in FcRγ−/− mice 36.