Protease-resistant proteins (HRP) induce more robust T cell proliferation than their degradation-sensitive counterparts (apo-HRP).

The harder a protein is to chop up, say Delamarre and colleagues on page 2049, the more vigorous an immune response it will trigger. This suggests that the most durable antigens—or those attached to degradation-resistant carrier proteins—might make the best vaccines.

The correlation between stability and immunogenicity may seem counterintuitive, given that the very products of lysosomal degradation—antigenic peptides or epitopes—bind to class II MHC molecules for presentation to CD4+ T cells. And many (but not all) in vitro studies show that blocking lysosomal function in vitro inhibits antigen presentation.

To determine which kind of antigen elicits the strongest immune response, Delamarre et al. stuck identical T or B cell epitopes into lysosomal degradation-resistant and degradation-sensitive versions of the same protein. Mice immunized with the more durable versions of the proteins generated more robust T cell and antibody responses than those immunized with the more degradable forms. Stabilizing the degradation-prone antigens using aldehyde fixation boosted their immunogenicity.

Antigen-presenting cells did not simply have a bigger appetite for the more stable form of the protein, as both forms were taken up equally well by dendritic cells (DCs). Rather, the more stable antigens were better retained in DCs as they transited from peripheral sites of antigen capture to lymph nodes, where they present their antigenic cargo to T cells.

This group previously showed that DCs express a paucity of proteases compared with macrophages, allowing them to degrade internalized proteins more slowly and thus retain them longer—perhaps explaining why DCs are so good at disseminating antigens and initiating immunity. Thus, both the nature of a protein and the cell type it ends up in help determine how immune provoking that protein will be.