Human influenza viruses and CD8+ T cell responses

doi:10.1016/j.coviro.2016.01.016

Current Opinion in Virology

Volume 16, February 2016, Pages 132-142

https://doi.org/10.1016/j.coviro.2016.01.016 Get rights and content

Highlights

•
Memory influenza-specific CD8⁺ T cells drive rapid recovery from influenza disease.
•
CD8⁺ T cell memory pools cross-react with distinct influenza strains.
•
Universal T cell vaccines may protect those at risk of severe influenza infection.
•
Vaccines must be assessed for longevity, coverage, viral escape and immunopathology.

Influenza A viruses (IAVs) cause significant morbidity and mortality worldwide, despite new strain-specific vaccines being available annually. As IAV-specific CD8⁺ T cells promote viral control in the absence of neutralizing antibodies, and can mediate cross-reactive immunity toward distinct IAVs to drive rapid recovery from both mild and severe influenza disease, there is great interest in developing a universal T cell vaccine. However, despite detailed studies in mouse models of influenza virus infection, there is still a paucity of data on human epitope-specific CD8⁺ T cell responses to IAVs. This review focuses on our current understanding of human CD8⁺ T cell immunity against distinct IAVs and discusses the possibility of achieving a CD8⁺ T cell mediated-vaccine that protects against multiple, distinct IAV strains across diverse human populations. We also review the importance of CD8⁺ T cell immunity in individuals highly susceptible to severe influenza infection, including those hospitalised with influenza, the elderly and Indigenous populations.

Section snippets

Human influenza viruses

Influenza viruses (IVs) belong to the Orthomyxoviridae family and are an enveloped virus, with a lipid bilayer encompassing an 8-stranded negative sense RNA genome that encodes 12 distinct proteins [1]. They comprise of three distinct families: A, B and C [2]. Influenza C viruses (ICV) generally cause a mild infection and thus are not typically considered a significant threat to population health. Conversely, influenza A viruses (IAV) and influenza B viruses (IBV) are responsible for seasonal

Severity of IAV disease

IAVs cause respiratory disease and are readily transmitted between humans by the inhalation of virus-containing aerosols produced through coughing or sneezing [5]. Furthermore, IAV is present in other animal hosts, in particular avian species, providing an additional reservoir for viral transmission. IAVs rapidly evolve through antigenic drift, whereby accumulating mutations in HA and NA glycoproteins result in evasion of pre-existing antibody responses [6]. This, together with the high

Adaptive immune control of IAV

Current IAV vaccines elicit humoral immunity directed toward the surface HA and NA glycoproteins and are highly effective in the control of IAV [29]. However, due to antigenic drift [6], these surface glycoproteins rapidly mutate, and thus humoral immunity established against one IAV strain is unlikely to protect against subsequent infections with distinct IAV strains [29]. Conversely, CD8⁺ T cells typically recognize the more conserved internal proteins of IAV, and thus have the potential to

Longevity of human CD8⁺ T cell memory pools

Cross-reactivity toward distinct IAV strains offers potential for universal immunity against influenza for as long as the established memory CD8⁺ T cell populations survive within an individual. Animal models have provided important insights into the persistence of CD8⁺ T cell memory. Influenza-specific CD8⁺ T cells can persist for the life-time of a laboratory mouse (2 years) when the animals are primed early (at 6 weeks) [55, 56]. However, until recently, there has been debate about the

The potential for an IAV-specific CD8⁺ T cell-mediated vaccine

The success of an IAV-specific T cell vaccine will depend greatly on selecting the best approach to achieve long-term, heterosubtypic protection across diverse human populations. The live-attenuated influenza vaccine, Flumist (MedImmune, Gaithersburg, MD), contains specific mutations in PB1 (K391E, E581G and A661T), PB2 (N265S) and NP (D34G), preventing viral replication at temperatures present within the human respiratory tract [63]. When given to children (aged 5–9), it induces limited T cell

Immunodominant CD8⁺ T cell epitopes in IAV

In order to provide protection across distinct ethnicities, a rationally designed vaccine would need to contain multiple viral peptides or peptide regions to elicit immunodominant CD8⁺ T cell responses restricted by a range of HLA alleles. To date, there have been 255 CD8⁺ T cell IAV-specific epitopes identified across 10 proteins using a range of epitope-identification techniques [72, 75] (reviewed in [78]). However, only a selected number of those influenza epitopes are immunogenic [53^••],

Targeted IAV vaccinations for at-risk populations

Certain groups, including the young, elderly, immunocompromised, pregnant and Indigenous populations, are particularly susceptible to IAV infection. It is important to understand the mechanisms underlying this heightened susceptibility in order to determine whether IAV vaccines need to be targeted toward these specific populations.

Conclusions

Although there is great interest in developing a CD8⁺ T cell-mediated IAV vaccine, there remains much to be learned about human influenza-specific CD8⁺ T cell responses. Recent studies suggest an important role for human CD8⁺ T cells in driving recovery from IAVs, especially the newly-emerged viruses with pandemic potential. However, we need a more in depth understanding of the magnitude, quality and clonal TCR characteristics of influenza-specific CD8⁺ T cells in order to design vaccines that

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

This work was supported by Australian National Health and Medical Research Council (NHMRC) Program Grant (AI1071916) to KK. KK is an NHMRC Career Development Fellow (CDF) 2 (1023294) and EBC is an NHMRC Peter Doherty Fellow. EJG is a recipient of an NHMRC Aboriginal and Torres Strait Islander Health Research Scholarship and Douglas and Lola Scholarship in Medical Science.

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¹: These authors contributed equally to this work.

View full text

Human influenza viruses and CD8+ T cell responses

Highlights

Section snippets

Human influenza viruses

Severity of IAV disease

Adaptive immune control of IAV

Longevity of human CD8+ T cell memory pools

The potential for an IAV-specific CD8+ T cell-mediated vaccine

Immunodominant CD8+ T cell epitopes in IAV

Targeted IAV vaccinations for at-risk populations

Conclusions

References and recommended reading

Acknowledgements

Cell Host Microbe

Vaccine

Microbes Infect/Inst Pasteur

Lancet

Lancet

Lancet

Virology

Lancet

Microbes Infect/Inst Pasteur

J Immunol

Proc Natl Acad Sci U S A

J Gen Virol

J Virol

Vaccine

Crit Rev Immunol

J Exp Med

Proc Natl Acad Sci U S A

Sci Transl Med

Introduction to molecular biology of influenza A viruses

Acta Biochim Pol

The influenza viruses

Med J Aust

Influenza type A in humans, mammals and birds: determinants of virus virulence, host-range and interspecies transmission

BioEssays

Influenza virus aerosols in the air and their infectiousness

Adv Virol

1918 influenza: the mother of all pandemics

Emerg Infect Dis

Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic

Nat Immunol

Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans

Science

Human infection with a novel avian-origin influenza A (H7N9) virus

N Engl J Med

A pandemic warning?

Nature

Two novel reassortants of avian influenza A (H5N6) virus in China

J Gen Virol

Origin and molecular characterization of the human-infecting H6N1 influenza virus in Taiwan

Protein Cell

Low pathogenic avian influenza A (H7N2) virus infection in immunocompromised adult, New York USA, 2003

Emerg Infect Dis

Novel avian influenza H7N3 strain outbreak, British Columbia

Emerg Infect Dis

Characterisation of an avian influenza A virus isolated from a human--is an intermediate host necessary for the emergence of pandemic influenza viruses?

Arch Virol

Influenza virus A (H10N7) in chickens and poultry abattoir workers, Australia

Emerg Infect Dis

Emerging influenza viruses and the prospect of a universal influenza virus vaccine

Biotechnol J

Mammalian adaptation of influenza A (H7N9) virus is limited by a narrow genetic bottleneck

Nat Commun

Airborne transmission of influenza A/H5N1 virus between ferrets

Science

Cytotoxic T-cell immunity to influenza

N Engl J Med

Cellular immune correlates of protection against symptomatic pandemic influenza

Nat Med

Recovery from severe H7N9 disease is associated with diverse response mechanisms dominated by CD8(+) T cells

Nat Commun

Complete modification of TCR specificity and repertoire selection does not perturb a CD8+ T cell immunodominance hierarchy

Proc Natl Acad Sci U S A

Oseltamivir prophylaxis reduces inflammation and facilitates establishment of cross-strain protective T cell memory to influenza viruses

PLOS ONE

Transgenic mice lacking class I major histocompatibility complex-restricted T cells have delayed viral clearance and increased mortality after influenza virus challenge

J Exp Med

Establishment and persistence of virus-specific CD4+ and CD8+ T cell memory

Human influenza viruses and CD8⁺ T cell responses

Longevity of human CD8⁺ T cell memory pools

The potential for an IAV-specific CD8⁺ T cell-mediated vaccine

Immunodominant CD8⁺ T cell epitopes in IAV

Complete modification of TCR specificity and repertoire selection does not perturb a CD8⁺ T cell immunodominance hierarchy

Establishment and persistence of virus-specific CD4⁺ and CD8⁺ T cell memory

Acute emergence and reversion of influenza A virus quasispecies within CD8⁺ T cell antigenic peptides

Multiple redundant effector mechanisms of CD8⁺ T cells protect against influenza infection