Response of dendritic cells to Mycobacterium tuberculosis infection and the induction of protective immunity using dendritic cells infected with an auxotrophic mutant of M. tuberculosis

• Main Author: Roy, Eleanor
• Published: University College London (University of London) 2005
• Subjects: 616.995014
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422346

Mycobacterium tuberculosis, the aetiological agent of tuberculosis, is an intracellular pathogen commonly infecting macrophages, and has also been shown to infect dendritic cells (DC). As DC are particularly effective antigen-presenting cells, it is likely that they play a principle role in initiating anti-mycobacterial T cell responses. This work investigates the activation of DC in response to M. tuberculosis infection using murine bone marrow-derived DCs, generated in the presence of granulocyte- macrophage colony-stimulating factor (GM-CSF). It was found that both unsorted DC populations and those sorted on CD11c+, were capable of supporting the survival and replication of wild type M. tuberculosis (H37Rv) in a manner similar to that observed in macrophages. Mycobacterial infection was found to be sufficient to activate the DC populations, particularly CD11c+ DC, to acquire a mature phenotype, as measured by cytokine production and expression of costimulatory and antigen presentation molecules on the cell surface. Further study showed that mycobacteria-infected DC could prime protective immunity in an experimental model of murine tuberculosis. This was carried out using a lysine auxotroph of M. tuberculosis. Infected DC were used to vaccinate syngeneic or allogeneic mice. Protection against challenge with wild type M. tuberculosis was observed in both cases, suggesting that recipient antigen-presenting cells crosspresented mycobacterial antigen from donor DC to induce a protective immune response. A similar protective response was observed on using a xenogeneic model, in which infected murine DC were used to vaccinate guinea pigs. Both CD4+ and CD8+ T cells harvested from spleens of vaccinated mice, showed specific production of interferon-y in response to mycobacterial antigen, indicating that crosspresentation by recipient antigen-presenting cells results in the effective priming of mycobacteria-specific T cells in vivo.