Boosting the Immune Response: The Use of iNKT cell ligands as vaccine adjuvants

Abstract

Natural killer T (NKT) cells comprise a small, but important T cell subset and are thought to bridge the innate and adaptive immune responses. The discovery of NKT cells and extensive research on their activating ligands have paved the way for modulation of these potent immunoregulatory cells in order to improve the outcome of various clinical conditions. Efforts to modulate NKT cell effector functions have ranged from therapy for influenza to anti-tumor immunotherapy. These approaches have also led to the use of NKT cell agonists such as α-Galactosylceramide (α-GalCer) and its analogs as vaccine adjuvants, an approach that is aimed at boosting specific B and T cell responses to a vaccine candidate by concomitant activation of NKT cells. In this review we will provide a comprehensive overview of the efforts made in using α-GalCer and its analogs as vaccine adjuvants. The diverse array of vaccination strategies used, as well as the role of NKT cell activating adjuvants will be discussed, with focus on vaccines against malaria, HIV, influenza and tumor vaccines. Collectively, these studies demonstrate the efficacy of NKT cell-specific agonists as adjuvants and further suggest that these compounds warrant serious consideration during the development of vaccination strategies.

Figure 1. The Role of NKT cell agonists as vaccine adjuvants

NKT cells can bridge innate and adaptive immune responses. NKT cells recognize lipid antigen in the context of CD1d molecules. Following activation, NKT cells rapidly secrete cytokines (i.e., IFN-g) and can directly mediate cytotoxicity. Cytokine production by NKT cells can lead to the activation of NK cells, macrophages (Mac) and in combination with CD40/CD40L interactions lead to the maturation of dendritic cells (DC). Thus, the co-administration of an NKT cell agonist, such as alpha galactosylceramide, with a vaccine may be able to enhance the efficacy of the vaccine by augmenting the magnitude of humoral and antigen-specific T cell responses.