Extracellular vesicles from Mycobacterium tuberculosis-infected neutrophils induce maturation of monocyte-derived dendritic cells and activation of antigen-specific Th1 cells.

Tuberculosis remains one of the leading public health problems in the world. The mechanisms that lead to the activation of the immune response against Mycobacterium tuberculosis (Mtb) have been extensively studied, with a focus on the role of cytokines as the main signals for immune cell communication. However, less is known about the role of other signals, such as extracellular vesicles (EVs), in the communication between immune cells, particularly during the activation of the adaptive immune response. In this study, we determined that EVs released by human neutrophils infected with Mtb (EV-Mtb) contained several host proteins that are ectosome markers. In addition, we demonstrated that EV-Mtb released after only 30 min of infection carried mycobacterial antigens and pathogen-associated molecular patterns, and we identified 15 mycobacterial proteins that were consistently found in high concentrations in EV-Mtb; these proteins contain epitopes for CD4 T cell activation. We found that EV-Mtb increased the expression of the co-stimulatory molecule CD80 and of the co-inhibitory molecule PD-L1 on immature monocyte-derived dendritic cells. We also found that immature and mature dendritic cells treated with EV-Mtb were able to induce IFN-γ production by autologous Mtb antigen-specific CD4 T cells, indicating that these EVs acted as antigen carriers and transferred mycobacterial proteins to the antigen-presenting cells. Our results provide evidence that EV-Mtb participate in the activation of the adaptive immune response against Mtb.