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Mycobacterium tuberculosis Antigens Specifically Modulate CCR2 and MCP-1/CCL2 on Lymphoid Cells from Human Pulmonary Hilar Lymph Nodes¹

Mauricio A. Arias^2,*, Gabriela Jaramillo^*, Yúrika P. López^*, Natalia Mejía^*, Camila Mejía^*, Adelis E. Pantoja^*, Robin J. Shattock, Luis F. García^* and George E. Griffin

^* Grupo de Inmunología Celular e Inmunogenética, Sede de Investigación Universitaria, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia; and Department of Cellular and Molecular Medicine, St George’s, University of London, London, United Kingdom

Macrophages and dendritic cells are involved in the immune response to Mycobacterium tuberculosis (Mtb). Such a response, although extensively studied using animal models and cells from human blood, has not been characterized in cells from pulmonary hilar lymph nodes (PHLN). We characterized populations of myeloid APC from PHLN and determined their expression of CCR2, CCR5, CCR7, CD40, CD54, CD80, and CD86 as well as the cytokine/chemokine microenvironment before and after purified protein derivative (PPD) and mannosilated lipoarabinomannan (ManLAM) stimulation. Results show that there are at least three APC populations in PHLN, defined as CD14^highHLA-DR^low/–, CD14^dimHLA-DR^dim, and CD14^–HLA-DR^high/dendritic cells (DC), with the largest number represented by CD14^dimHLA-DR^dim cells (where dim indicates intermediate levels). CD14^–HLA-DR^high/DC expressed higher levels of costimulatory molecules and lower levels of CCR2 and CCR5, but all cell populations showed similar CCR7 levels. PPD and ManLAM specifically down-regulated CCR2 expression but not that of CCR5 and CCR7, and such down-regulation was observed on all APC populations. Mtb Ag did not affect the expression of costimulatory molecules. PPD but not ManLAM specifically induced MCP-1/CCL2 production, which was likely associated with the induction of IFN- because this cytokine was highly induced by PPD. We characterized, for the first time, different APC from human PHLN and show that Mtb Ag exert fine and specific regulation of molecules closely associated with the immune response to Mtb infection. Because knowledge of this response in secondary lymphoid tissues is still poorly understood in humans, such studies are necessary and important for a better understanding of lymphoid cell microenvironment and migrating capacities and their role in the immunopathogenesis of tuberculosis.

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 study was supported by a Wellcome Trust International Fellowship (no. 068707).

² Address correspondence and reprint requests to Dr. Mauricio A. Arias, Department of Cellular and Molecular Medicine, St George’s, University of London, London SW17 0RE, United Kingdom. E-mail address: marias{at}sgul.ac.uk

³ Abbreviations used in this paper: Mtb, Mycobacterium tuberculosis; CM, complete medium; DC, dendritic cell; dim, intermediate (level); LN, lymph node; ManLAM, mannosilated lipoarabinomannan; MDC, monocyte derived chemokine; MFI, mean fluorescence intensity; MNC, mononuclear cell; PHLN, pulmonary hilar lymph node; PHS, pooled human serum; PPD, purified protein derivative; SI, stimulation index; TB, tuberculosis.