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Review
. 2020 Oct 20:11:2172.
doi: 10.3389/fimmu.2020.02172. eCollection 2020.

Modulation of Immune Responses to Influenza A Virus Vaccines by Natural Killer T Cells

John P Driver  1 , Darling Melany de Carvalho Madrid  1 , Weihong Gu  1 , Bianca L Artiaga  2 , Jürgen A Richt  2
Affiliations
Review

Modulation of Immune Responses to Influenza A Virus Vaccines by Natural Killer T Cells

John P Driver et al. Front Immunol. .

Abstract

Influenza A viruses (IAVs) circulate widely among different mammalian and avian hosts and sometimes give rise to zoonotic infections. Vaccination is a mainstay of IAV prevention and control. However, the efficacy of IAV vaccines is often suboptimal because of insufficient cross-protection among different IAV genotypes and subtypes as well as the inability to keep up with the rapid molecular evolution of IAV strains. Much attention is focused on improving IAV vaccine efficiency using adjuvants, which are substances that can modulate and enhance immune responses to co-administered antigens. The current review is focused on a non-traditional approach of adjuvanting IAV vaccines by therapeutically targeting the immunomodulatory functions of a rare population of innate-like T lymphocytes called invariant natural killer T (iNKT) cells. These cells bridge the innate and adaptive immune systems and are capable of stimulating a wide array of immune cells that enhance vaccine-mediated immune responses. Here we discuss the factors that influence the adjuvant effects of iNKT cells for influenza vaccines as well as the obstacles that must be overcome before this novel adjuvant approach can be considered for human or veterinary use.

Keywords: adjuvant; immune modulation; influenza A virus; natural killer T (NKT) cells; vaccines.

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Figures

Figure 1
Figure 1
Invariant natural killer T cells activate and regulate innate and adaptive immune responses that enhance influenza A virus (IAV) vaccine immunity. The co-administered IAV vaccine antigens and the selected α-GalCer analog are internalized by dendritic cells that simultaneously present the α-GalCer analog on CD1d to iNKT cells and IAV epitopes on major histocompatibility complex (MHC) II to CD4+ T cells. Cytokines secreted by iNKT cells increase MHC class II and CD40 presentation to naïve CD4+ T cells, which generates follicular T helper cells (TFH) that provide non-cognate help to B cells. iNKT cells also undergo indirect activation in response to proinflammatory cytokines released by IAV-stimulated antigen-presenting cells (APCs), with or without engagement of the iNKT TCR by CD1d-presented self-antigens. iNKT cell-licensed dendritic cells (DCs) generate vaccine-specific CD8+ T cells which become further activated by cytokines secreted by α-GalCer and IAV-stimulated APCs as well as iNKT cells and CD4+ T cells. The iNKT cells recognizing α-GalCer on DCs differentiate into iNKT follicular helper (iNKTFH) cells that provide cognate help to B cells specific for vaccine antigens. iNKT cells also boost humoral immunity by trans-activating natural killer cells that can stimulate B cells to secrete immunoglobulin G.
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