Exosomes Derived from M. Bovis BCG Infected Macrophages Activate Antigen-Specific CD4+ and CD8+ T Cells In Vitro and In Vivo

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.

Regulation of chronic inflammatory and immune processes by extracellular vesicles

“…For example, EVs derived from Mycobacterium bovis Bacillus Calmette Guérin-infected macrophages promote T cell immunity in mice in the presence of DCs, whereas EVs from Toxoplasma gondii-pulsed DCs can confer protection against parasite infection in mice (33)(34)(35). EVs from CMV-infected epithelial cells stimulate memory CD4 + T cells in a DC-dependent manner.…”

Myeloma as a model for the process of metastasis: implications for therapy

“…[93][94][95][96][97][98][99] Exosomes are small nanometer-sized (50-100 nm) vesicles of endocytic origin, which are released in the extracellular milieu by several cell types. [100][101][102][103][104][105][106][107][108][109] Previous studies have shown the intriguing role of exosomes in tumor progression because of the ability of tumor cell-derived exosomes to modulate and mold the host microenvironment, thereby promoting tumor cell growth and disease progression. [110][111][112][113] Although preparation of the premetastatic niche has not been studied in MM, we recently showed in preliminary data that stromal cells present in contact with MM cells secrete exosomes that modulate the growth and dissemination potential of MM cells.…”

Cell-Cell Communication Via Extracellular Membrane Vesicles and Its Role in the Immune Response

“…Notably, exosomes derived from macrophages infected with an intracellular pathogen, such as Mycobacterium tuberculosis or Mycobacterium bovis, shed exosomes that are transmitted to distant DCs, leading to presentation of pathogenspecific antigens to CD4 + T cells and DC maturation. Similarly, exosomes derived from endothelial cells infected with cytomegalovirus (CMV) convey CMV-specific antigens to DCs to activate CD4 + T cells (Giri and Schorey, 2008;Walker et al, 2009).…”