CD4+ T Cell-derived IL-10 Promotes Brucella abortus Persistence via Modulation of Macrophage Function |
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Authors: | Mariana N. Xavier Maria G. Winter Alanna M. Spees Kim Nguyen Vidya L. Atluri Teane M. A. Silva Andreas J. B?umler Werner Müller Renato L. Santos Renée M. Tsolis |
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Affiliation: | 1. Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, California, United States of America.; 2. Departamento de Clínica e Cirurgia Veterinárias, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.; 3. Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.; Yale University School of Medicine, United States of America, |
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Abstract: | Evasion of host immune responses is a prerequisite for chronic bacterial diseases; however, the underlying mechanisms are not fully understood. Here, we show that the persistent intracellular pathogen Brucella abortus prevents immune activation of macrophages by inducing CD4+CD25+ T cells to produce the anti-inflammatory cytokine interleukin-10 (IL-10) early during infection. IL-10 receptor (IL-10R) blockage in macrophages resulted in significantly higher NF-kB activation as well as decreased bacterial intracellular survival associated with an inability of B. abortus to escape the late endosome compartment in vitro. Moreover, either a lack of IL-10 production by T cells or a lack of macrophage responsiveness to this cytokine resulted in an increased ability of mice to control B. abortus infection, while inducing elevated production of pro-inflammatory cytokines, which led to severe pathology in liver and spleen of infected mice. Collectively, our results suggest that early IL-10 production by CD25+CD4+ T cells modulates macrophage function and contributes to an initial balance between pro-inflammatory and anti-inflammatory cytokines that is beneficial to the pathogen, thereby promoting enhanced bacterial survival and persistent infection. |
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