Harnessing NKT cells for vaccination

  Natural killer T (NKT) cells are innate-like T cells capable of enhancing both innate and adaptive immune responses. When NKT cells are stimulated in close temporal association with co-administered antigens, strong antigen-specific immune responses can be induced, prompting the study of NKT cell agonists as novel immune adjuvants. This activity has been attributed to the capacity of activated NKT cells to act as universal helper cells, with the ability to provide molecular signals to dendritic cells and B cells that facilitate T cell and antibody responses, respectively. These signals can override the requirement for conventional CD4+ T cell help, so that vaccines can be designed without need to consider CD4+ T cell repertoire and MHC class II diversity. Animal studies have highlighted some drawbacks of the approach, namely concerns around induction of NKT cell hyporesponsiveness, which may limit vaccine boosting, and potential for toxicity. Here we highlight studies that suggest these obstacles can be overcome by targeted delivery in vivo. We also feature new studies that suggest activating NKT cells can help encourage differentiation of T cells into tissue resident memory cells that play an important role in prophylaxis against infection, and may be required in cancer therapy. Lay Summary Vaccine-induced immune responses generally involve activation of immune cells called T cells and B cells which have a variety of mechanisms to limit infection. Each T or B cell has a randomly generated receptor for binding pathogen-derived antigens, but only a few cells with an individual’s repertoire of cells will recognise a given pathogen; the aim of vaccination is therefore to induce these few cells to undergo significant division to meet the demands of eliminating infection. However, some T cells called natural killer T (NKT) cells have receptors of similar structure that recognise specific glycolipids, and are found in high numbers in the tissues where immune reactions take place. Here we describe studies that show that these glycolipids can be added to vaccines to activate NKT cells, which has the net effect of improving vaccine responses. This is because NKT cells are poised to provide molecular signals that initiate a cascade of cellular interactions that ultimately improve the capacity of pathogen-specific T cells and B cells to divide and function. We describe different techniques that can be used to incorporate these compounds into vaccines, some limitations on their use, and new strategies to overcome these limitations.