Background | Recent evidence suggests that adjuvant-mediated cell death contributes to adjuvant activities.
Results | We found that the prototypical adjuvant, alum, triggers a novel form of cathepsin-mediated necrosis. We found that agents that trigger this cell death pathway trigger, like alum, a Th2-biased immune response. We also found that inhibiting this cell death pathway prevented adjuvant-mediated immunity.
Conclusion | Selective induction of necrosis is a powerful inducer of adaptive immunity.
Significance | Understanding how adjuvant-mediated necrotic cell death controls immunity should improve the design of more powerful but safe adjuvants.
Immunologic adjuvants are critical components of vaccines, but it remains unclear how prototypical adjuvants enhance the adaptive immune response.Recent studies have shown that necrotic cells could trigger an immune response. Although most adjuvants have been shown to be cytotoxic, this activity has traditionally been considered a side effect. We set out to test the role of adjuvant-mediated cell death in immunity and found that alum, the most commonly used adjuvant worldwide, triggers a novel form of cell death in myeloid leukocytes characterized by cathepsin-dependent lysosome disruption. We demonstrated that direct lysosome permeabilization with a soluble peptide, Leu-Leu-OMe, mimics the alumlike form of necrotic cell death in terms of cathepsin dependence and cell-type specificity. Using a combination of a haploid genetic screen and cathepsin-deficient cells, we identified specific cathepsins that control lysosome-mediated necrosis. We identified cathepsin C as critical for Leu-Leu-OMe-induced cell death, whereas cathepsins B and S were required for alum-mediated necrosis. Consistent with a role of necrotic cell death in adjuvant effects, Leu-Leu-OMe replicated an alum-likeimmune response in vivo, characterized by dendritic cell activation, granulocyte recruitment, and production of Th2-associated antibodies. Strikingly, cathepsin C deficiency not only blocked Leu-Leu-OMe-mediated necrosis but also impaired Leu-Leu-OMe-enhanced immunity. Together our findings suggest that necrotic cell death is a powerful mediator of a Th2-associated immune response.