Increased Immunogenicity Through Autophagy

For many infectious diseases, CD4 T cell mediated T helper-1 (Th1) type immunity is a major protective mechanism. CD4 T cells also play a protective role against tuberculosis since HIV-1 induced depletion of CD4 T cells predisposes to fatal tuberculosis. Indeed, tuberculosis due to Mycobacterium tuberculosis kills
around 1.5 million people per year and infects a third of humankind. Both subunit vaccines and a live attenuated Bacillus Calmette Guerin (BCG) have been used inducing immunity against tuberculosis in humans.
BCG vaccination is widely used during childhood in developing countries and is the safest vaccine known to humans. BCG induces CD4 and CD8 T cell dependent Th1 immunity and protects against childhood tuberculosis, but is poorly effective against adult tuberculosis. An intriguing property of intracellular BCG is the “maturation arrest,” where the vaccine is sequestered within an immature phagosome, which does not fuse with lysosomes. This affects the ability of antigen presenting cells (macrophages and dendritic cells; APCs) to produce peptide epitopes from BCG and reduces CD4 T cell responses. We describe here that rapamycin can be used to induce autophagy in APCs, enhancing the delivery of BCG vaccine phagosomes and their secreted Antigen 85B into autophagosomes and then to proteolytic lysosome compartments of APCs.
This process leads to increased peptide presentation by APCs to CD4 T cells. Overexpression of secreted Ag85B in recombinant BCG leads to rapamycin independent activation of aggresomes in the cytosol, which also triggers autophagy, and boosts antigen presentation. Consistent with intracellular effects, rapamycin activated dendritic cells containing BCG are more effective as vaccines in mice against tuberculosis. Finally, coadministration of rapamycin with BCG given to mice enhances both CD4 and CD8 T cell responses, which protects better against a challenge with tuberculosis. Autophagy, therefore, is a novel mechanism to increase vaccine efficacy.