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

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.

SUBMITTER: Driver JP

PROVIDER: S-EPMC7606973 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Driver John P JP de Carvalho Madrid Darling Melany DM Gu Weihong W Artiaga Bianca L BL Richt Jürgen A JA

Frontiers in immunology 20201020

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, w ...[more]

PMID: 33193296

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Project description:Abstract Background Influenza A virus (IAV) infection leads to significant morbidity and mortality. Biological sex influences the immune responses to IAV infection, resulting in higher mortality in women of reproductive age. Previous studies revealed increased activation of T and B cells in female mice after IAV infection, but extensive analysis of sex differences in both innate and adaptive immune cells over time is lacking. Invariant natural killer T (iNKT) cells are fast‐reacting forces and modulators of immune responses that are important to IAV immunity, but it is not known if the presence and function of iNKT cells differ between females and males. The aim of this study was to determine immunological mechanisms that contribute to the increased disease severity in female mice during IAV infection. Methods Female and male mice were infected with mouse‐adapted IAV and monitored for weight loss and survival. Immune cell populations and cytokine expression in bronchoalveolar lavage fluid, lung, and mediastinal lymph node were determined at three time points after infection using flow cytometry and ELISA. Results The results reveal increased severity and mortality in adult female mice compared to age‐matched males. Female mice show larger increases in innate and adaptive immune cell populations and cytokine production in lung compared to mock on Day 6 postinfection. On Day 9 postinfection, female mice express higher numbers of iNKT cells in lung and liver compared to males. Conclusions This comprehensive analysis of immune cells and cytokines over time following IAV infection reveals increased leukocyte expansion and stronger proinflammatory cytokine responses in female mice during disease initiation. Furthermore, this is the first study to report a sex bias in iNKT cell populations after IAV infection. The data suggests that the process of recovery from IAV‐induced airway inflammation is associated with increased expansion of several different iNKT cell subpopulations in female mice. In this study, comprehensive profiling of innate and adaptive immune cells following influenza A virus infection over time in adult female and male mice was performed. The data reveals higher numbers of lung leukocytes and increased cytokine production in female mice at the onset of symptom progression. Additionally, female mice show a sex‐dependent expansion of invariant natural killer T cell populations in lung at the start of disease recovery. Highlights Infection with influenza A virus (IAV) leads to increased weight loss and mortality in female mice. IAV infection induces increased leukocyte expansion and stronger proinflammatory cytokine responses in the lung of female mice compared to mock on Day 6 postinfection. IAV infection leads to a sex‐specific increase of invariant natural killer T (iNKT) cell populations in lung and liver of female mice on Day 9 postinfection. The association between weight gain and the sex‐specific increase in iNKT cells on Day 9 postinfection implicate a role for iNKT cells in the resolution of inflammation in female mice.

Project description:BackgroundInfluenza infects tens of millions of people every year in the USA. Other than notable risk groups, such as children and the elderly, it is difficult to predict what subpopulations are at higher risk of infection. Viral challenge studies, where healthy human volunteers are inoculated with live influenza virus, provide a unique opportunity to study infection susceptibility. Biomarkers predicting influenza susceptibility would be useful for identifying risk groups and designing vaccines.MethodsWe applied cell mixture deconvolution to estimate immune cell proportions from whole blood transcriptome data in four independent influenza challenge studies. We compared immune cell proportions in the blood between symptomatic shedders and asymptomatic nonshedders across three discovery cohorts prior to influenza inoculation and tested results in a held-out validation challenge cohort.ResultsNatural killer (NK) cells were significantly lower in symptomatic shedders at baseline in both discovery and validation cohorts. Hematopoietic stem and progenitor cells (HSPCs) were higher in symptomatic shedders at baseline in discovery cohorts. Although the HSPCs were higher in symptomatic shedders in the validation cohort, the increase was statistically nonsignificant. We observed that a gene associated with NK cells, KLRD1, which encodes CD94, was expressed at lower levels in symptomatic shedders at baseline in discovery and validation cohorts. KLRD1 expression in the blood at baseline negatively correlated with influenza infection symptom severity. KLRD1 expression 8 h post-infection in the nasal epithelium from a rhinovirus challenge study also negatively correlated with symptom severity.ConclusionsWe identified KLRD1-expressing NK cells as a potential biomarker for influenza susceptibility. Expression of KLRD1 was inversely correlated with symptom severity. Our results support a model where an early response by KLRD1-expressing NK cells may control influenza infection.

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

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

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