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) 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.
Highlights
Macrophages are key players in major chronic inflammatory diseases including tuberculosis, atherosclerosis and rheumatoid arthritis
Infection with mycobacteria results in a host response which results in the formation of granulomas, highly organized structures characterized by the presence of macrophages, which are considered to rely solely on invariant immune receptors
TCRab bearing macrophages accumulate in human tuberculosis granulomas and anti-TNF treatment of macrophages results in downregulation of the TCRab, which is associated with caspase 3 cleavage and suppression of TCRj
Summary
Macrophages are key players in major chronic inflammatory diseases including tuberculosis, atherosclerosis and rheumatoid arthritis. Based on their myeloid origin and professional phagocytic activity they are traditionally regarded as a pillar of innate immunity [1]. The disease is caused by mycobacteria that are efficiently contained by macrophages in highly organized immune structures, the tuberculous granulomas. Ample evidence indicates that the generation and maintenance of tuberculous granulomas require TNF [3,4]. Reactivation of the disease by therapeutic TNF blockade is associated with disruption of the granuloma architecture that leads to spreading of the mycobacteria into the surrounding tissue [5]
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