IgG1 is pathogenic in Leishmania mexicana infection.

There are >2 million new cases of leishmaniasis annually, and no effective vaccine has been developed to prevent infection. In murine infection, Leishmania mexicana, which lives intracellularly in host macrophages, has developed pathways to hijack host IgG to induce a suppressive IL-10 response through FcγRs, the cell-surface receptors for IgG. To guide vaccine development away from detrimental Ab responses, which can accompany attempts to induce cell-mediated immunity, it is crucial to know which isotypes of IgG are pathogenic in this infection. We found that IgG1 and IgG2a/c induce IL-10 from macrophages in vitro equally well but through different FcγR subtypes: IgG1 through FcγRIII and IgG2a/c through FcγRI primarily, but also through FcγRIII. In sharp contrast, mice lacking IgG1 develop earlier and stronger IgG2a/c, IgG3, and IgM responses to L. mexicana infection and yet are more resistant to the infection. Thus, IgG1, but not IgG2a/c or IgG3, is pathogenic in vivo, in agreement with prior studies indicating that FcγRIII is required for chronic disease. This calls into question the assumption that macrophages, which should secrete IL-10 in response to IgG1 and IgG2a/c immune complexes, are the most important source of IL-10 generated by IgG-FcγR engagement in L. mexicana infection. Further investigations are required to better determine the cell type responsible for this immunosuppressive FcγRIII-induced IL-10 pathway and whether IgG2a/c is protective.

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

FcRgamma and interleukin-10 (IL-10) are both required for chronic disease in C57BL/6 mice with Leishmania mexicana parasite infection. FcRgamma 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 FcgammaRIII in other systems. To begin to dissect the mechanisms by which FcgammaRs contribute to chronic disease, we infected FcgammaRIII knockout (KO) mice with L. mexicana. We show that FcgammaRIII 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 FcgammaRIII 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 FcgammaRIII KO mice compared to that of B6 controls. Furthermore, macrophages from FcgammaRIII KO and FcRgamma 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 FcgammaRIII, as well as parasite-mediated inhibition of IL-12 and induction of IL-10, independent of FcgammaR. Our data demonstrate a specific role for FcgammaRIII in suppressing protective immunity in L. mexicana infection, likely through macrophage IL-10 production in the lesion.