Blocking acid, boosting T cells

Intracellular antacids boost cytotoxic T cell responses, according to a study on page 817. Accapezzato and colleagues show that an inhibitor that prevents endosome acidification enhances presentation of antigens to CD8⁺ T cells and boosts vaccine responses.

Many vaccines are made of soluble proteins derived from viruses or bacteria. But these vaccines tend to be poor stimulators of CD8⁺ T cells, as soluble antigens are primarily degraded in acidified endosomes; the resulting peptides are loaded onto MHC class II molecules and presented to CD4⁺ helper T cells. But in certain cell types, exogenous antigen can escape from endosomes and enter the cytosol. From there, the antigen can infiltrate the class I MHC processing pathway—which is normally reserved for internally synthesized proteins—and be cross-presented to CD8⁺ T cells.

Accapezzato and colleagues now show that cross-presentation is enhanced when antigen-pulsed dendritic cells are treated with chloroquine, a widely used antimalarial drug that prevents endosome acidification. The enhancement was due to both decreased antigen degradation and increased escape of antigen into the cytosol. The latter finding is consistent with a recent study showing that chloroquine can increase membrane permeability.

A single dose of oral chloroquine given to recipients of hepatitis B virus booster shots resulted in detectable CD8⁺ T cell responses in nearly 70% of the recipients, compared with no responses in those who received the shot alone. This readily available drug might thus be a useful T cell–boosting supplement to soluble antigen vaccines.