Boosting vaccine efficacy the natural (killer) way

Abstract

Coordination of the innate and adaptive immune systems is paramount to the development of protective humoral and cellular immunity following vaccination. Natural killer (NK) cells are front-line soldiers of the innate immune system, and recent studies have revealed functions for NK cells in long-lived immune memory and the regulation of adaptive immune responses. These findings suggest that NK cells may play important roles in the development of efficacious vaccines, as well as, in some contexts, failed immunizations. Here, we review the current understanding of the immunomodulatory and memory differentiation capabilities of NK cells. We examine the context dependency of the mechanisms and the nature of NK cell-mediated modulation of the immune response, and discuss how these insights may impact immunization strategies and the development of next-generation vaccines.

Keywords: immune regulation; natural killer cells; vaccination.

Figure 1. NK cells in the priming of an immune response

During a primary response, NK cells can directly interact with and positively or negatively regulate antigen presenting cells (APCs) and downstream T cell responses. NK cells can also interact directly with T cells and, at least indirectly, with B cells to modulate the magnitude of T- and B-cell responses. All of these interactions can shape the memory precursor pool of T and B cells that form following contraction of the primary response. More work needs to be done to decipher the NK-cell receptors and mechanisms involved in NK-cell regulation of adaptive cell populations. In some contexts, memory NK cells have been shown to develop, although here as well, the NK receptors delineating memory NK from other NK cells are largely unknown.

Figure 2. NK cells in recall and re-infection

In a recall response, memory T and B cell populations respond more quickly and expand more rapidly than in a primary response. Thus, memory T cell-derived cytokines can contribute to activation of NK cells. Whether memory T and B cells remain as amenable to NK cell regulation as their naive counterparts has not been determined. Memory NK cells may also contribute through rapid effector functions or enhanced ADCC function with antibodies from memory B cells. Additionally, there is essentially nothing known about the regulatory capacities of memory NK cell populations and whether they represent another, more specialized subset capable of modulating adaptive immunity or possess another distinct function.