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.
Thomas
Bolaji N
BN
Department of Medicine, Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6073, USA.
Buxbaum
Laurence U
LU
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D007074:Immunoglobulin G / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007894:Leishmania mexicana / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000172:deficiency / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology
C485700:Fcgr3 protein, mouse; D007074:Immunoglobulin G; D017452:Receptors, IgG; D016753:Interleukin-10; D007371:Interferon-gamma