While this enhances Ag presentation by DCs and thereby augments T-cell responses
as described in detail in the section “Modulation of T-cell responses by FcR engagement,” it is likely that the lysosomal targeting of Salmonella has also a direct protective effect. This is supported by the fact that passive immunization by transfer of Salmonella-specific Abs protects mice from lethal challenge with Salmonella as mice without specific Ab transfer succumbed to challenge infection within the first week, a time frame that would not allow the generation of an effective T-cell response 81, 82. We therefore propose that, as for Legionella, Mycobacterium, and Toxoplasma infection, specific Abs mediate protection against Salmonella by targeting the bacteria Fluorouracil molecular weight into lysosomes where they are degraded. While the link between Ab-mediated protection, FcR engagement, and lysosomal localization of the pathogen has only been made for a few infectious agents, reports about other pathogens point toward this being
a more general mechanism active against intracellular pathogens. For instance, Ab-mediated targeting into lysosomes has been reported for the intracellular bacterium Rickettsia conorii and the protozoan parasite Encephalitozoon cuniculi; both pathogens evade phagolysosomal fusion in the absence of specific Abs 83,
84. Furthermore, macrophage killing of Chlamydia was shown to be strongly C59 wnt concentration enhanced in the presence of Abs 38. We therefore propose that Abs can directly mediate protection against intracellular pathogens by cross-linking host cell FcγRs. This induces a signaling cascade that activates the host cell and thereby interferes with Non-specific serine/threonine protein kinase the evasion of phagolysosomal fusion by the pathogen, resulting in pathogen degradation (Fig. 1). The importance of Ab–FcR interactions has long been recognized for ADCC and the induction of oxidative burst; however, the panel of effector functions modulated and induced by this interaction is far more diverse than originally thought and of great importance in immune responses against intracellular pathogens. On the one hand, Ab–FcR interactions have a great impact on the magnitude and the functional characteristics of T-cell responses, which have long been recognized to be important in mediating protection against intracellular pathogens. On the other hand, Ag–Ab complexes can stimulate the host cell through FcRs which may render them nonpermissive for intracellular pathogen replication (in particular for those that have evolved strategies to evade intracellular degradation) and mediate killing of these pathogens.