IL-33 drives alum-induced cytokine production and provides a robust secondary antibody response independently of alum (CCR4P.211)

Abstract

Abstract For over 80 years, human vaccines have used aluminium-based adjuvants (alum) despite incomplete understanding of how alum enhances the immune response. One proposed mechanism is that alum induces cellular necrosis and release of endogenous danger signals. These signals induce inflammation-associated cytokines that lead to humoral immunity. IL-33 is proposed to be released from necrotic cells and can elicit TH2-biased cytokines. Therefore, we investigated a role for IL-33 in the adjuvant activity of alum. We show that alum induces cellular necrosis and elevates IL-33 levels shortly after intraperitoneal administration. Alum or IL-33 injection induces similar significant increases in IL-5, IL-6, KC, MCP-1 and MIP-1β. We establish that many of the alum-induced cytokines are dependent on IL-33 using IL-33 knockout mice or an IL-33-neutralizing recombinant ST2 receptor. Interestingly, IL-33 itself can function as an adjuvant. While IL-33 only induces a marginal primary response, it facilitates a secondary response comparable to alum and correlates with delayed splenic germinal center formation. Alum-induced antibody responses in IL-33 knockout mice are similar to those in wild-type mice, demonstrating that IL-33 is not absolutely required for the alum-induced humoral response. Our results provide novel insights into the mechanism of action behind alum-induced cytokine responses and show that IL-33 is sufficient to provide a robust secondary antibody response independently of alum.