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A TNF-regulated recombinatorial macrophage immune receptor implicated in granuloma formation in tuberculosis.

ABSTRACT: Macrophages play a central role in host defense against mycobacterial infection and anti- TNF therapy is associated with granuloma disorganization and reactivation of tuberculosis in humans. Here, we provide evidence for the presence of a T cell receptor (TCR) ?? based recombinatorial immune receptor in subpopulations of human and mouse monocytes and macrophages. In vitro, we find that the macrophage-TCR?? induces the release of CCL2 and modulates phagocytosis. TNF blockade suppresses macrophage-TCR?? expression. Infection of macrophages from healthy individuals with mycobacteria triggers formation of clusters that express restricted TCR V? repertoires. In vivo, TCR?? bearing macrophages abundantly accumulate at the inner host-pathogen contact zone of caseous granulomas from patients with lung tuberculosis. In chimeric mouse models, deletion of the variable macrophage-TCR?? or TNF is associated with structurally compromised granulomas of pulmonary tuberculosis even in the presence of intact T cells. These results uncover a TNF-regulated recombinatorial immune receptor in monocytes/macrophages and demonstrate its implication in granuloma formation in tuberculosis.

SUBMITTER: Beham AW

PROVIDER: S-EPMC3219713 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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A TNF-regulated recombinatorial macrophage immune receptor implicated in granuloma formation in tuberculosis.

Beham Alexander W AW Puellmann Kerstin K Laird Rebecca R Fuchs Tina T Streich Roswita R Breysach Caroline C Raddatz Dirk D Oniga Septimia S Peccerella Teresa T Findeisen Peter P Kzhyshkowska Julia J Gratchev Alexei A Schweyer Stefan S Saunders Bernadette B Wessels Johannes T JT Möbius Wiebke W Keane Joseph J Becker Heinz H Ganser Arnold A Neumaier Michael M Kaminski Wolfgang E WE

PLoS pathogens 20111117 11

Macrophages play a central role in host defense against mycobacterial infection and anti- TNF therapy is associated with granuloma disorganization and reactivation of tuberculosis in humans. Here, we provide evidence for the presence of a T cell receptor (TCR) αβ based recombinatorial immune receptor in subpopulations of human and mouse monocytes and macrophages. In vitro, we find that the macrophage-TCRαβ induces the release of CCL2 and modulates phagocytosis. TNF blockade suppresses macrophage ...[more]

PMID: 22114556

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Project description:The mechanisms underlying abnormal granuloma formation in patients with sarcoidosis are complex and remain poorly understood. A novel in vitro human granuloma model was used to determine the molecular mechanisms of granuloma genesis in patients with sarcoidosis in response to putative disease-causing mycobacterial antigens. Peripheral blood mononuclear cells (PBMCs) from patients with active sarcoidosis and from normal, disease-free control subjects were incubated for 7 days with purified protein derivative-coated polystyrene beads. Molecular responses, as reflected by differential expression of genes, extracellular cytokine patterns, and cell surface receptor expression, were analyzed. Unbiased systems biology approaches were used to identify signaling pathways engaged during granuloma formation. Model findings were compared with human lung and mediastinal lymph node gene expression profiles. Compared with identically treated PBMCs of control subjects (n = 5), purified protein derivative-treated sarcoidosis PBMCs (n = 6) were distinguished by the formation of cellular aggregates resembling granulomas. Ingenuity Pathway Analysis of differential expression gene patterns identified molecular pathways that are primarily regulated by IL-13, which promotes alternatively activated (M2) macrophage polarization. M2 polarization was further demonstrated by immunohistochemistry performed on the in vitro sarcoidosis granuloma-like structures. IL-13-regulated gene pathways were confirmed in human sarcoidosis lung and mediastinal lymph node tissues. The in vitro human sarcoidosis granuloma model provides novel insights into early granuloma formation, particularly IL-13 regulation of molecular networks that regulate M2 macrophage polarization. M2 macrophages are predisposed to aggregation and multinucleated giant cell formation, which are characteristic features of sarcoidosis granulomas. Clinical trial registered with www.clinicaltrials.gov (NCT01857401).

Dataset Information

A TNF-regulated recombinatorial macrophage immune receptor implicated in granuloma formation in tuberculosis.

Publications

A TNF-regulated recombinatorial macrophage immune receptor implicated in granuloma formation in tuberculosis.

Similar Datasets

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