Impact of intracellular location of and antigen display by intracellular bacteria: implications for vaccine development.

Intracellular bacteria are primarily controlled by T-lymphocytes. The 'phagosomal' bacteria such as Salmonella enterica and Mycobacterium bovis BCG remain in the phagosome. These microbes primarily stimulate CD4 T-cells via antigen presentation through MHC class II molecules. In contrast, Listeria monocytogenes egresses from the phagosome into the cytoplasm by virtue of listeriolysin. This 'cytoplasmic' pathogen is controlled by CD8 T-cells through MHC class I antigen presentation. Some bacterial pathogens such as Mycobacterium tuberculosis presumably remain in the phagosome but apparently 'perforate' the phagosomal membrane and thus stimulate both CD4 and CD8 T-cells. We have constructed S. enterica and M. bovis BCG vaccine carriers which secrete listeriolysin. Such constructs are capable of introducing antigens into the MHC class II and MHC class I pathway, resulting in stimulation of both CD4 and CD8 T-cells. Moreover, we constructed S. enterica vaccines which display one and the same listerial antigen in secreted and somatic form. Secreted antigen display was found to be superior to somatic antigen display. Hence, we consider antigen secretion a major prerequisite of an effective vaccine against intracellular bacteria.