A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis

PLoS Pathogens

Julia Kzhyshkowska¹  Stefan Schweyer¹  Kerstin Puellmann²  Dirk Raddatz³  Joseph Keane⁴  Johannes T. Wessels⁵  Alexander W. Beham⁶  Rebecca Laird⁶  Wolfgang E. Kaminski⁶  Roswita Streich⁶  Caroline Breysach⁶  Septimia Oniga⁷  Teresa Peccerella⁷  Tina Fuchs⁷  Peter Findeisen⁷  Alexei Gratchev⁸  Bernadette Saunders⁸  Heinz Becker⁹  Wiebke Möbius^1,10  Arnold Ganser^1,11  Michael Neumaier^1,11 

[1] Department of Dermatology, University of Heidelberg Medical Faculty Mannheim, Mannheim, Germany;Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Hannover, Germany;Department of Medicine, University of Göttingen, Göttingen, Germany;Department of Nephrology/Rheumatology, University of Göttingen, Göttingen, Germany;Department of Pathology, University of Göttingen, Göttingen, Germany;Department of Surgery, University of Göttingen, Göttingen, Germany;Institute for Clinical Chemistry, University of Heidelberg Medical Faculty Mannheim, Mannheim, Germany;Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, Russia;Max-Planck-Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany;Medicine, Central Clinical School, Centenary Institute of Cancer Medicine and Cell Biology, Sydney, Australia;Trinity College Dublin, Institute of Molecular Medicine, College Green, Dublin, Ireland

关键词: Macrophages;    Granulomas;    Monocytes;    Mycobacterium tuberculosis;    T cells;    Phagocytosis;    Mouse models;    Mycobacterium bovis;   

DOI  :  10.1371/journal.ppat.1002375

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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-TCRαβ expression. Infection of macrophages from healthy individuals with mycobacteria triggers formation of clusters that express restricted TCR Vβ repertoires. In vivo, TCRαβ 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-TCRαβ 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.

【 授权许可】

CC BY