Abstract
BackgroundThe persistence of Mycobacterium leprae (M. leprae) infection is largely dependent on the types of host immune responses being induced. Macrophage, a crucial modulator of innate and adaptive immune responses, could be directly infected by M. leprae. We therefore postulated that M. leprae-infected macrophages might have altered immune functions.Methodology/Principal FindingsHere, we treated monocyte-derived macrophages with live or killed M. leprae, and examined their activation status and antigen presentation. We found that macrophages treated with live M. leprae showed committed M2-like function, with decreased interleukin 1 beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNF-alpha) and MHC class II molecule expression and elevated IL-10 and CD163 expression. When incubating with naive T cells, macrophages treated with live M. leprae preferentially primed regulatory T (Treg) cell responses with elevated FoxP3 and IL-10 expression, while interferon gamma (IFN-gamma) expression and CD8+ T cell cytotoxicity were reduced. Chromium release assay also found that live M. leprae-treated macrophages were more resistant to CD8+ T cell-mediated cytotoxicity than sonicated M. leprae-treated monocytes. Ex vivo studies showed that the phenotype and function of monocytes and macrophages had clear differences between L-lep and T-lep patients, consistent with the in vitro findings.Conclusions/SignificanceTogether, our data demonstrate that M. leprae could utilize infected macrophages by two mechanisms: firstly, M. leprae-infected macrophages preferentially primed Treg but not Th1 or cytotoxic T cell responses; secondly, M. leprae-infected macrophages were more effective at evading CD8+ T cell-mediated cytotoxicity.
Highlights
The ability of an intracellular pathogen to establish a productive infection relies on its ability to evade cytotoxic T cell-mediated clearance of infected cells
We found that macrophages treated with live M. leprae showed committed M2-like function, with decreased interleukin 1 beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNF-alpha) and MHC class II molecule expression and elevated IL-10 and CD163 expression
We investigated the immune status of macrophages stimulated with live M. leprae or killed M. leprae
Summary
The ability of an intracellular pathogen to establish a productive infection relies on its ability to evade cytotoxic T cell-mediated clearance of infected cells. In the case of Mycobacterium leprae (M. leprae), an obligate intracellular pathogen that is dependent on the host fatty acid metabolism for microbial lipid synthesis[1], the outcome of M. leprae-caused leprosy is strongly associated with the types of immune responses being activated[2]. At one end of the spectrum, the lepromatous leprosy (L-lep) is a progressive disease with numerous lesions, plenty of intracellular bacteria, and is associated with weak or absent cellular immunity and increased FoxP3+ T cells at lesion site[3,4,5,6]. M2-type macrophages can be activated by IL-4, IL-13, and/or IL-10 stimulation and were thought to induce regulatory responses through IL-10 production, with downregulated MHC class II and upregulated CD163 expression. We postulated that M. leprae-infected macrophages might have altered immune functions.
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