Research Article: Mycobacterium leprae-Infected Macrophages Preferentially Primed Regulatory T Cell Responses and Was Associated with Lepromatous Leprosy

Date Published: January 11, 2016

Publisher: Public Library of Science

Author(s): Degang Yang, Tiejun Shui, Jake W. Miranda, Danny J. Gilson, Zhengyu Song, Jia Chen, Chao Shi, Jianyu Zhu, Jun Yang, Zhichun Jing, Carlos Franco-Paredes.

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.

Partial Text: 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[3–6]. In contrast, the tuberculoid leprosy (T-lep) at the other end of the spectrum is a self-contained disease with fewer lesions, low or undetectable intracellular bacteria, and is associated with robust Th1-skewing antigen-specific cellular immunity[7,8]. Therefore, it is believed that host immune systems dictate the clinical outcome of M. leprae infections.

In this study, we presented a comparative analyses of live vs. killed M. leprae in stimulation of macrophages. Live M. leprae-infected macrophages had significantly higher IL-10 and CD163 expression and lower MHC class II expression, whereas killed M. leprae-treated macrophages had significantly higher IL-1beta, IL-12 and TNF-alpha, compared to untreated macrophages, demonstrating a difference in the polarization of macrophages by live and killed M. leprae. Furthermore, this difference in polarization was preserved even after the removal of live M. leprae and restimulation with killed M. leprae, suggesting that the differentiation toward M2 differentiation was committed. Previous studies treating whole PBMCs with live BCG vaccine have found that live BCG vaccines induced regulatory T cell phenotype and function[4,16]. Here, by treating PBMC components separately, we found that M. leprae, live or killed, did not act on naive T cells directly. Rather, through treatment of macrophages with live or killed M. leprae, different types of T cell responses were primed. Live M. leprae-treated macrophages preferentially induced regulatory T cell phenotypes and resulted in reduced CD8+ T cell cytotoxicity. Finally, these trends were conserved in leprosy patients, especially in the lesion site macrophages.



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