FcγRIII mediates IgG-induced IL-10 and is required for chronic Leishmania lesions (51.2)

Abstract

Abstract Chronic disease caused by the protozoan parasite Leishmania mexicana, requires IL-10 and the common γ chain (FcRγ) shared by the activating IgG receptors FcγRI, III, and IV and by FcαR and FcεR. FcRγ can also take the place of CD3ζ in some T cells. Which pathway is responsible for IL-10 production and suppression of a protective immune response is unknown. We recently showed that FcγRIII KO mice, like IL-10 and FcRγ KO mice, resolve L. mexicana lesions with a stronger Th1 response and much lower parasite burdens (by 4–5 logs) than WT mice. We now show that FcγRIII KO macrophages have a severe IL-10 defect, when induced by IgG-opsonized parasites, and that this defect is comparable to FcRγ KO macrophages. Thus FcγRIII appears to contribute most of the IgG-induced IL-10, supporting the in vivo findings. We also found that anti-Leishmania IgG responses (IgG1 and IgG2a) were not altered in FcγRIII KO mice compared to WT mice, consistent with the model that parasite-bound IgG alters T cell development and thus may determine the strength of the Th1 response rather than the reverse. Furthermore, depletion of CD25+ T cells did not change the chronic nature of L. mexicana lesions, nor was T cell IL-10 production from FcγRIII KO mice lower than from B6 mice. When taken together these findings support a model in which macrophage FcγRIII, rather than Treg cells, provides the IL-10 that suppresses a protective immune response to L. mexicana.