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Tuberculosis Triggers a Tissue-Dependent Program of Differentiation and Acquisition of Effector Functions by Circulating Monocytes¹

Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

The origin and function of the different myeloid cell subsets that appear in the lung during pulmonary tuberculosis are unknown. Herein we show that adoptively transferred monocytes give rise to many of the macrophage and dendritic cell (DC) subsets that appear following aerosol infection with virulent Mycobacterium tuberculosis. Monocyte differentiation in infected peripheral tissue is surprisingly heterogeneous and results in the formation of five distinct myeloid subsets, including both classically activated macrophages, that produce inducible NO synthase via an IFN--dependent mechanism, and DC. In contrast, monocytes recruited to draining pulmonary lymph nodes are functionally different and acquire a mature DC phenotype. Thus, while monocytes are recruited to the lungs of uninfected mice, their differentiation and acquisition of myeloid effector functions are dramatically altered in the presence of inflammation and bacteria and are dependent on tissue localization. Therefore, our results support a model in which recruited monocytes are well poised to influence multiple aspects of host immunity to infections in the lungs. This report provides the first direct evidence for monocyte differentiation into both the macrophage and DC lineages in vivo following infection with a live human pathogen.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 HL80312 and HL080330 to S.M.B. M.S. is a recipient of an Arthritis Foundation Postdoctoral Fellowship.

² Current address: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Box 280, SE-171 77 Stockholm, Sweden.

³ Address correspondence and reprint requests to Dr. Markus Sköld, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Box 280, SE-171 77 Stockholm, Sweden. E-mail address: markus.skold{at}ki.se or Dr. Samuel M. Behar, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Smith Building Room 516C, One Jimmy Fund Way, Boston, MA 02115. E-mail address: sbehar{at}rics.bwh.harvard.edu

⁴ Abbreviations used in this paper: Mtb, Mycobacterium tuberculosis; BM, bone marrow; DC, dendritic cell; FSC, forward light scatter; iNOS, inducible NO synthase; MCP, monocyte chemoattractant protein; M, macrophage; MFI, mean fluorescence intensity; PEC, peritoneal exudate cells; PLN, pulmonary lymph node; TG, thioglycolate; Tip-DC, TNF and iNOS producing DC; WT, wild type.

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