Abstract
Activation of both CD4+ and CD8+ T cells is required for an effective immune response to an M. tuberculosis infection. However, infected macrophages are poor antigen presenting cells and may be spatially separated from recruited T cells, thus limiting antigen presentation within a granuloma. Our previous studies showed that infected macrophages release from cells small membrane-bound vesicles called exosomes which contain mycobacterial lipid components and showed that these exosomes could stimulate a pro-inflammatory response in naïve macrophages. In the present study we demonstrate that exosomes stimulate both CD4+ and CD8+ splenic T cells isolated from mycobacteria-sensitized mice. Although the exosomes contain MHC I and II as well as costimulatory molecules, maximum stimulation of T cells required prior incubation of exosomes with antigen presenting cells. Exosomes isolated from M. bovis and M. tuberculosis infected macrophages also stimulated activation and maturation of mouse bone marrow-derived dendritic cells. Interestingly, intranasal administration of mice with exosomes isolated from M. bovis BCG infected macrophages induce the generation of memory CD4+ and CD8+ T cells. The isolated T cells also produced IFN-γ upon restimulation with BCG antigens. The release of exosomes from infected macrophages may overcome some of the defects in antigen presentation associated with mycobacterial infections and we suggest that exosomes may be a promising M. tuberculosis vaccine candidate.
Highlights
Granulomas are required for controlling an M. tuberculosis (Mtb) infection and the site of a chronic inflammatory response
We previously reported that exosomes released from infected macrophages contain mycobacterial glycolipids; protein composition was not evaluated in these studies [13]
Work by Schaible et al demonstrated that apoptotic vesicles obtained from Mtb infected macrophages contain mycobacterial antigens and can stimulate MHC class I and CD1b restricted T cells
Summary
Granulomas are required for controlling an M. tuberculosis (Mtb) infection and the site of a chronic inflammatory response. Granuloma formation requires CD4+ T cells as mice deficient in these cells fail to form granulomas or control the infection [1]. Activated CD4+ T cells migrate to the site of infection and produce cytokines and chemokines, especially IFN-c, which serves to recruit and activate macrophages promoting granuloma formation and the inflammatory process [4]. CD8+ T cells are required for maintaining an effective immune response at later stages of infection [5] [4]. This requires processing of mycobacterial antigens and presentation onto class I MHC by cells within the granuloma
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