title: Mycobacterium tuberculosis infection of human dendritic cells decreases integrin expression, adhesion and migration to chemokines.
abstract: Tuberculosis (TB) remains a major global health problem accounting for millions of deaths annually. Approximately one-third of the world's population is infected with the causative agent Mycobacterium tuberculosis. The onset of an adaptive immune response to M. tuberculosis is delayed compared with other microbial infections. This delay permits bacterial growth and dissemination. The precise mechanism(s) responsible for this delay have remained obscure. T-cell activation is preceded by dendritic cell (DC) migration from infected lungs to local lymph nodes and synapsis with T cells. We hypothesized that M. tuberculosis may impede the ability of DCs to reach lymph nodes and initiate an adaptive immune response. We used primary human DCs to determine the effect of M. tuberculosis on expression of heterodimeric integrins involved in cellular adhesion and migration. We also evaluated the ability of infected DCs to adhere to and migrate through lung endothelial cells, which is necessary to reach lymph nodes. We show by flow cytometry and confocal microscopy that M. tuberculosis-infected DCs exhibit a significant reduction in surface expression of the β(2) (CD18) integrin. Distribution of integrin β(2) is also markedly altered in M. tuberculosis-infected DCs. A corresponding reduction in the αL (CD11a) and αM (CD11b) subunits that associate with integrin β(2) was also observed. Consistent with reduced integrin surface expression, we show a significant reduction in adherence to lung endothelial cell monolayers and migration towards lymphatic chemokines when DCs are infected with M. tuberculosis. These findings suggest that M. tuberculosis modulates DC adhesion and migration to increase the time required to initiate an adaptive immune response.
authors: Department of Pathology, Microbiology, & Immunology, University of South Carolina School of Medicine, Columbia, SC, USA.
authors: Lawton L
authors: LL
authors: Roberts
authors: Cory M
authors: CM
authors: Robinson
mesh_terms: D000293:Adolescent; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D018925:Chemokines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D016023:Integrins / Q000276:immunology*; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology* / Q000473:pathology
chemical_list: D018925:Chemokines; D016023:Integrins
keywords: CD18; dendritic cells; integrins; migration; mycobacteria
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