IL-33 regulates the immune response to particulate vaccine adjuvants

Abstract

Vaccines are one of the most successful tools contributing to global health. Despite their success, further research into safe and efficient vaccination is required to address two key issues; to combat emerging infectious agents and to overcome the suboptimal protection conferred by several existing vaccines. Currently there is a move towards subunit vaccines, which do not use whole organisms but instead incorporate specific antigens into formulations containing adjuvants. The role of the adjuvant is to increase vaccine efficacy by enhancing or directing antigen-specific responses. Alum was the first adjuvant used in non-living human vaccines and it remains the most commonly used adjuvant worldwide. However, the mechanisms underlying the immunomodulatory properties of alum have not been fully elucidated. Despite being a potent driver of humoral immune responses, alum is a relatively poor driver of cellular immunity. In recent years polymeric micro- and nano-particles have been increasingly investigated as vaccine adjuvants with the potential to induce cellular immunity and consequently may find application in the development of vaccines against intracellular pathogens and cancer. Since particulate adjuvants are generally not pattern-associated molecular patterns it is likely that danger-associated molecular patterns play a key role in particulate driven innate and adaptive immunity. Frequently referred to as a DAMP or alarmin, the cytokine IL-33 was first identified in 2005, as a potent initiator of T helper type 2 polarization. Recent discoveries have extended the range of functions for IL-33 beyond type 2 conditions and its role as an alarmin at barrier sites, with emerging roles for IL-33 in Th1 responses and T cell regulation. Here the role of IL-33 as a regulator of alum and nanoparticulate adjuvant induced cellular immunity was addressed. This research found that following intramuscular injection, alum is inducing the recruitment of monocytes, neutrophils and CD25+ Foxp3+ T cells to the site of injection, as well as IL-10 productive from the spleen indicating that alum is inducing immune suppression. Upon investigation, alum was found to be a weak inducer of antigen-specific CD8+ T cell responses but a potent inducer of humoral immunity following intramuscular injection. IL-33 and ST2 were found to play no role in alum-induced cellular immunity. In opposition to alum, polystyrene nanoparticles did not drive the recruitment of CD25+ Foxp3+ T cells to the site of injection, but were indeed found to be excellent drivers of antigen-specific CD8+ T cell responses and IFNƴ production. In striking contrast to the literature, IL-33 and ST2 were found to be negative regulators of nanoparticle-induced antigen-specific T cell responses.