Leishmania amazonensis induces a nonhealing infection in C3H mice, whereas infection with Leishmania major is self-healing. We found that C3H mice infected with L. amazonensis exhibited decreased IL-12 production, which could account for the susceptibility to this organism. However, exogenous IL-12 administration failed to induce a healing immune response. The failure of L. amazonensis-infected C3H mice to respond to IL-12 was associated with a specific defect in IL-12 receptor β2 (IL-12Rβ2) mRNA expression by CD4+ T cells. Furthermore, decreased IL-12Rβ2 mRNA expression correlated with a decrease in the IL-12-signaling capacity of the lymph node (LN) cells. IL-4 did not contribute to susceptibility or down-regulation of the IL-12Rβ2 subunit, because IL-4−/− mice remained susceptible to L. amazonensis infection, even after IL-12 administration, and CD4+ cells from infected IL-4−/− mice also had reduced expression of IL-12Rβ2 mRNA. These results demonstrate that regulation of the IL-12 receptor, independent of IL-4, is a point of control for the immune response to leishmaniasis. In contrast to experimental L. major infections, where host genetics control susceptibility, these studies demonstrate that the lack of IL-12 responsiveness may be dictated by the pathogen, rather than the host.
Infection of C57BL/6 (B6) mice with
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 Fc␥RIII in other systems. To begin to dissect the mechanisms by which Fc␥Rs contribute to chronic disease, we infected Fc␥RIII knockout (KO) mice with L. mexicana. We show that Fc␥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␥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␥RIII KO mice compared to that of B6 controls. Furthermore, macrophages from Fc␥RIII 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 Fc␥RIII, as well as parasite-mediated inhibition of IL-12 and induction of IL-10, independent of Fc␥R. Our data demonstrate a specific role for Fc␥RIII in suppressing protective immunity in L. mexicana infection, likely through macrophage IL-10 production in the lesion.
C3H mice infected with Leishmania mexicana fail to develop a protective Th1 response, and are unable to cure. In this study, we show that L. mexicana cysteine proteases suppress the antileishmanial immune response. Previous studies demonstrated that deletion of the entire multicopy cysteine protease B (CPB) gene array in L. mexicana is associated with decreased parasite virulence, potentially attributable to factors related to parasite fitness rather than to direct effects on the host immune response. We now show that C3H mice infected with the L. mexicana deletion mutant (Δcpb) initially develop lesions that grow at rates comparable to those of wild-type L. mexicana-infected mice. However, in contrast to controls, Δcpb-induced lesions heal with an accompanying Th1 immune response. Lesion resolution was Th1 dependent, as Δcpb-infected IL-12p40−/− and STAT4−/− mice developed high parasite burdens and progressive disease. Moreover, when L. major was transfected with a cosmid expressing multiple L. mexicana CPB genes, this parasite induced a significantly lower IFN-γ response compared with wild-type L. major. These data indicate that cysteine proteases of L. mexicana are critical in suppressing protective immune responses and that inhibition of CPB may prove to be a valuable immunomodulatory strategy for chronic forms of leishmaniasis.
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