Abstract
BackgroundTuberculosis is one of the world’s leading killers, stealing 1.4 million lives and causing 8.7 million new and relapsed infections in 2011. The only vaccine against tuberculosis is BCG which demonstrates variable efficacy in adults worldwide. Human infection with Mycobacterium tuberculosis results in the influx of inflammatory cells to the lung in an attempt to wall off bacilli by forming a granuloma. Gr1intCD11b+ cells are called myeloid-derived suppressor cells (MDSC) and play a major role in regulation of inflammation in many pathological conditions. Although MDSC have been described primarily in cancer their function in tuberculosis remains unknown. During M. tuberculosis infection it is crucial to understand the function of cells involved in the regulation of inflammation during granuloma formation. Understanding their relative impact on the bacilli and other cellular phenotypes is necessary for future vaccine and drug design.Methodology/Principal FindingsWe compared the bacterial burden, lung pathology and Gr1intCD11b+ myeloid-derived suppressor cell immune responses in M. tuberculosis infected NOS2-/-, RAG-/-, C3HeB/FeJ and C57/BL6 mice. Gr-1+ cells could be found on the edges of necrotic lung lesions in NOS2-/-, RAG-/-, and C3HeB/FeJ, but were absent in wild-type mice. Both populations of Gr1+CD11b+ cells expressed high levels of arginase-1, and IL-17, additional markers of myeloid derived suppressor cells. We then sorted the Gr1hi and Gr1int populations from M. tuberculosis infected NOS-/- mice and placed the sorted both Gr1int populations at different ratios with naïve or M. tuberculosis infected splenocytes and evaluated their ability to induce activation and proliferation of CD4+T cells. Our results showed that both Gr1hi and Gr1int cells were able to induce activation and proliferation of CD4+ T cells. However this response was reduced as the ratio of CD4+ T to Gr1+ cells increased. Our results illustrate a yet unrecognized interplay between Gr1+ cells and CD4+ T cells in tuberculosis.
Highlights
Tuberculosis is the primary cause of death from a bacterial disease, and is further exacerbated by the very extensive incidence of latent disease, as well as the emergence of drugresistant forms of the bacillus [1,2]
The results of this study provide further evidence that cells expressing intermediate levels of the Gr1 marker are a predominant subset of cells accumulating in the lungs of mice developing lung necrosis due to their inability to control infection with M. tuberculosis, whereas these cells appear to be in low numbers in infected wild-type mice devoid of necrosis formation
We demonstrated this in NOS2 -/- mice and C3HeB/FeJ mice, and in Rag2 -/- mice, the latter indicating that this response was independent of the need to generate acquired immunity
Summary
Tuberculosis is the primary cause of death from a bacterial disease, and is further exacerbated by the very extensive incidence of latent disease, as well as the emergence of drugresistant forms of the bacillus [1,2]. During M. tuberculosis infection it is crucial to understand the function of cells involved in the regulation of inflammation during granuloma formation Understanding their relative impact on the bacilli and other cellular phenotypes is necessary for future vaccine and drug design. Methodology/Principal Findings: We compared the bacterial burden, lung pathology and Gr1intCD11b+ myeloidderived suppressor cell immune responses in M. tuberculosis infected NOS2-/-, RAG-/-, C3HeB/FeJ and C57/BL6 mice. Gr-1+ cells could be found on the edges of necrotic lung lesions in NOS2-/-, RAG-/-, and C3HeB/FeJ, but were absent in wild-type mice. Both populations of Gr1+CD11b+ cells expressed high levels of arginase-1, and IL-17, additional markers of myeloid derived suppressor cells. Our results illustrate a yet unrecognized interplay between Gr1+ cells and CD4+ T cells in tuberculosis
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