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FcRIII Mediates Immunoglobulin G-Induced Interleukin-10 and Is Required for Chronic Leishmania mexicana Lesions

Department of Medicine, Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,¹ VA Medical Center, Philadelphia, Pennsylvania 19104²

Received 26 February 2007/ Returned for modification 16 April 2007/ Accepted 27 November 2007

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

Published ahead of print on 10 December 2007.

Editor: J. F. Urban, Jr.