FcγRIII mediates immunoglobulin G-induced interleukin-10 and is required for chronic Leishmania mexicana lesions

FcR gamma and interleukin-10 (IL-10) are both required for chronic disease in C57BL/6 mice with Leishmania mexicana parasite infection. FcR gamma is a component of several different FcRs and may be a component of some T-cell receptors. The initial antibody response to L. mexicana is an immunoglobulin G1 (IgG1) response, and IgG1 preferentially binds to Fc gamma RIII in other systems. To begin to dissect the mechanisms by which Fc gamma Rs contribute to chronic disease, we infected Fc gamma RIII knockout (KO) mice with L. mexicana. We show that Fc gamma RIII KO mice are resistant to L. mexicana infection, resolving lesions in association with a stronger gamma interferon response, similar to IL-10 KO mice, with parasite control by 12 weeks. We found that the Leishmania-specific IgG response is unaltered in Fc gamma RIII KO mice compared with that in wild-type controls. The frequencies of IL-10 production from lymph node CD25(+) CD4(+) T cells are the same in KO and wild-type mice, and depletion of CD25(+) cells did not alter the course of infection, implying that T-reg cells may not be the mechanism for susceptibility to L. mexicana infection, unlike for L. major infection. However, IL-10 mRNA was greatly diminished in the lesions of Fc gamma RIII KO mice compared to that of B6 controls. Furthermore, macrophages from Fc gamma RIII KO and FcR gamma KO mice have the same profound defect in IL-10 production induced by IgG-opsonized amastigotes. We also found IL-10-dependent (major) and -independent (minor) inhibition of IL-12 mediated by Fc gamma RIII, as well as parasite-mediated inhibition of IL-12 and induction of IL-10, independent of Fc gamma R. Our data demonstrate a specific role for Fc gamma RIII in suppressing protective immunity in L. mexicana infection, likely through macrophage IL-10 production in the lesion.