Key Points
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Natural killer T (NKT) cells are lymphocytes that express a T-cell receptor (TCR) and markers of NK cells. Unlike conventional T cells, NKT cells recognize glycolipids that are presented in association with non-polymorphic CD1d molecules.
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Most NKT cells (invariant NKT cells; iNKT cells) express a semi-invariant TCR α-chain: Vα14–Jα18 in mice and Vα24–Jα18 in humans. This is paired with a limited number of β-chains: Vβ11 in humans and Vβ2, Vβ7 or Vβ8 in mice.
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iNKT cells can be activated by either endogenous glycosphingolipids or by exogenous microbial ligands. iNKT-cell activation through TCR stimulation can be enhanced by inflammatory cytokines that are secreted by antigen-presenting cells (APCs).
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iNKT-cell activation results in TCR downregulation, proliferation and secretion of T helper 1 (TH1)- and (TH2)-type cytokines. Activated iNKT cells induce dendritic cell (DC) and B-cell maturation as well as NK-cell activation, ultimately bridging the innate and adaptive arms of the immune response.
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iNKT cells regulate various immune responses, including tumour immunosurveillance, autoimmunity and the response to several microbial pathogens (bacteria, viruses, fungi and parasites).
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iNKT-cell activation can be manipulated both in vitro and in vivo by using synthetic agonists (such as α-galactosylceramide) that have different binding affinities. Co-injection of iNKT-cell agonists and model antigens results in the expansion of antigen-specific B-cell and T-cell responses, and this has prompted the use of NKT-cell agonists as vaccine adjuvants in the clinical setting.
Abstract
To optimize vaccination strategies, it is important to use protocols that can 'jump-start' immune responses by harnessing cells of the innate immune system to assist the expansion of antigen-specific B and T cells. In this Review, we discuss the evidence indicating that invariant natural killer T (iNKT) cells can positively modulate dendritic cells and B cells, and that their pharmacological activation in the presence of antigenic proteins can enhance antigen-specific B- and T-cell responses. In addition, we describe structural and kinetic analyses that assist in the design of optimal iNKT-cell agonists that could be used in the clinical setting as vaccine adjuvants.
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We apologize to those colleagues whose data we have been unable to cite owing to space limitations. We thank A. Stock for critical reading of the manuscript.
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Glossary
- Prime–boost vaccination
-
Repeated immunizations that are administered when a single application of a vaccine is insufficient, using the same vaccine preparation (homologous prime–boost) or using different vaccine preparations (heterologous prime–boost) to sequentially stimulate a stronger immune response. Prior exposure to one vaccine strain can elicit antibody and T-cell responses to shared epitopes following exposure to a second vaccine strain, increasing the efficacy of heterologous prime–boost regimens.
- B16 melanoma
-
A widely used experimental mouse melanoma. B16 melanoma is poorly immunogenic and therefore is difficult to eliminate. Largely because of this, B16 melanoma is a good model for testing cancer immunotherapies.
- Cytokine storm
-
A strong systemic immune response that results in the release of high levels of inflammatory mediators (such as cytokines, oxygen free radicals and coagulation factors). Both pro-inflammatory cytokines (such as tumour-necrosis factor, interleukin-1 (IL-1) and IL-6) and anti-inflammatory cytokines (such as IL-10 and IL-1 receptor antagonist) are increased in the serum of patients experiencing a cytokine storm.
- T-cell anergy
-
A state of T-cell unresponsiveness to stimulation with antigen. T-cell anergy can be induced by stimulation with a large amount of specific antigen in the absence of the engagement of co-stimulatory molecules.
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Cerundolo, V., Silk, J., Masri, S. et al. Harnessing invariant NKT cells in vaccination strategies. Nat Rev Immunol 9, 28–38 (2009). https://doi.org/10.1038/nri2451
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DOI: https://doi.org/10.1038/nri2451
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