Cutting Edge: CD4 T Cells Generated from Encounter with Seasonal Influenza Viruses and Vaccines Have Broad Protein Specificity and Can Directly Recognize Naturally Generated Epitopes Derived from the Live Pandemic H1N1 Virus

Richards, Katherine A.; Topham, David J.; Chaves, Francisco A.; Sant, Andrea J.

doi:10.4049/jimmunol.1001395

Cited by 72 publications

(76 citation statements)

References 18 publications

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“…Depending on the study and region analyzed, individuals under the age of 25 years represented 45% to 60% of infected subjects, though the pathogenic effects of H1N1 virus infection were most pronounced in individuals more than 60 years old (4,36). These findings, as well as recent immunological studies from our laboratory and other laboratories (11,17,20,22,25,33,39,48,51,52,55,61,62), suggest that previous encounters with vaccines or viruses provide immunological advantages and immunological memory in the population despite the "serological distance" between the hemagglutinin (HA) and neuraminidase (NA) proteins of seasonal and pandemic strains.…”

supporting

confidence: 61%

Infection with Seasonal Influenza Virus Elicits CD4 T Cells Specific for Genetically Conserved Epitopes That Can Be Rapidly Mobilized for Protective Immunity to Pandemic H1N1 Influenza Virus

Alam

Sant

2011

J Virol

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In recent years, influenza viruses with pandemic potential have been a major concern worldwide. One unresolved issue is how infection or vaccination with seasonal influenza virus strains influences the ability to mount a protective immune response to novel pandemic strains. In this study, we developed a mouse model of primary and secondary influenza infection by using a widely circulating seasonal H1N1 virus and the pandemic strain of H1N1 that emerged in Mexico in 2009, and we evaluated several key issues. First, using overlapping peptide libraries encompassing the entire translated sequences of 5 major influenza virus proteins, we assessed the specificity of CD4 T cell reactivity toward epitopes conserved among H1N1 viruses or unique to the seasonal or pandemic strain by enzyme-linked immunospot (ELISpot) assays. Our data show that CD4 T cells reactive to both virus-specific and genetically conserved epitopes are elicited, allowing separate tracking of these responses. Populations of cross-reactive CD4 T cells generated from seasonal influenza infection were found to expand earlier after secondary infection with the pandemic H1N1 virus than CD4 T cell populations specific for new epitopes. Coincident with this rapid CD4 T cell response was a potentiated neutralizing-antibody response to the pandemic strain and protection from the pathological effects of infection with the pandemic virus. This protection was not dependent on CD8 T cells. Together, our results indicate that exposure to seasonal vaccines and infection elicits CD4 T cells that promote the ability of the mammalian host to mount a protective immune response to pandemic strains of influenza virus.

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supporting

confidence: 61%

Infection with Seasonal Influenza Virus Elicits CD4 T Cells Specific for Genetically Conserved Epitopes That Can Be Rapidly Mobilized for Protective Immunity to Pandemic H1N1 Influenza Virus

Alam

Sant

2011

J Virol

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“…Since human T-cells specific for seasonal IAVs also display strong cross-reactivity with IAVs of other subtypes (Jameson et al, 1999;Kreijtz et al, 2008;Lee et al, 2008) and pH1N1 2009 viruses (Richards et al, 2010;Tu et al, 2010), it can be hypothesized that individuals with a history of IAV infection were protected from pH1N1 virus infections to a certain extent. This would imply that young children that are supposedly immunologically naïve for IAV would be more at risk for developing severe disease.…”

Section: T-cells Provide Protection Against Infection With Ph1n1mentioning

confidence: 99%

Cross-protective immunity against influenza pH1N1 2009 viruses induced by seasonal influenza A (H3N2) virus is mediated by virus-specific T-cells

Hillaire

Trierum

Kreijtz

et al. 2011

Journal of General Virology

113

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Influenza A (H1N1) viruses of swine origin were introduced into the human population in 2009 and caused a pandemic. The disease burden in the elderly was relatively low, which was attributed to the presence of cross-reacting serum antibodies in this age group, which were raised against seasonal influenza A (H1N1) viruses that circulated before 1957. It has also been described how infection with heterosubtypic influenza viruses can induce some degree of protection against infection by a novel strain of influenza virus. Here, we assess the extent of protective immunity against infection with the 2009 influenza A (H1N1) pandemic influenza virus that is afforded by infection with a seasonal influenza A (H3N2) virus in mice. Mice that experienced a primary A (H3N2) influenza virus infection displayed reduced weight loss after challenge infection and cleared the 2009 influenza A (H1N1) virus infection more rapidly. To elucidate the correlates of protection of this heterosubtypic immunity to pandemic H1N1 virus infection, adoptive transfer experiments were carried out by using selected post-infection lymphocyte populations. Virus-specific CD8+ T-cells in concert with CD4+ T-cells were responsible for the observed protection. These findings may not only provide an explanation for epidemiological differences in the incidence of severe pandemic H1N1 infections, they also indicate that the induction of cross-reactive virus-specific CD8+ and CD4+ T-cell responses may be a suitable approach for the development of universal influenza vaccines.

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“…ELISpot assays were performed as previously described (56,57). Ninety-six-well filter plates (Millipore) were coated with 5 g/ml purified anti-ferret IFN-␥ (clone MTF14; MabTech) in PBS overnight and then washed and blocked with cell culture medium 2 .…”

Section: Ferret Elispot Assaysmentioning

confidence: 99%

Flow Cytometric and Cytokine ELISpot Approaches To Characterize the Cell-Mediated Immune Response in Ferrets following Influenza Virus Infection

DiPiazza

Richards

Batarse

et al. 2016

J Virol

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Influenza virus infections represent a significant socioeconomic and public health burden worldwide. Although ferrets are considered by many to be ideal for modeling human responses to influenza infection and vaccination, efforts to understand the cellular immune response have been severely hampered by a paucity of standardized procedures and reagents. In this study, we developed flow cytometric and T cell enzyme-linked immunosorbent spot (ELISpot) approaches to characterize the leukocyte composition and antigen-specific T cell response within key lymphoid tissues following influenza virus infection in ferrets. Through a newly designed and implemented set of serological reagents, we used multiparameter flow cytometry to directly quantify the frequency of CD4؉ and CD8 ؉ T cells, Ig ؉ B cells, CD11b ؉ myeloid-derived cells, and major histocompatibility complex (MHC) class II-positive antigen-presenting cells (APCs) both prior to and after intranasal infection with A/California/ 04/09 (H1N1). We found that the leukocyte composition was altered at 10 days postinfection, with notable gains in the frequency of T cells and myeloid cells within the draining lymph node. Furthermore, these studies revealed that the antigen specificity of influenza virus-reactive CD4 and CD8 T cells was very broad, with recognition of the viral HA, NA, M1, NS1, and NP proteins, and that total reactivity to influenza virus postinfection represented approximately 0.1% of the circulating peripheral blood mononuclear cells (PBMC). Finally, we observed distinct patterns of reactivity between individual animals, suggesting heterogeneity at the MHC locus in ferrets within commercial populations, a finding of considerable interest in efforts to move the ferret model forward for influenza vaccine and challenge studies. IMPORTANCEFerrets are an ideal animal model to study transmission, diseases, and vaccine efficacies of respiratory viruses because of their close anatomical and physiological resemblances to humans. However, a lack of reagents has limited our understanding of the cell-mediated immune response following infection and vaccination. In this study, we used cross-reactive and ferret-specific antibodies to study the leukocyte composition and antigen-specific CD4 and CD8 T cell responses following influenza A/California/04/09 (H1N1) virus infection. These studies revealed strikingly distinct patterns of reactivity between CD4 and CD8 T cells, which were overlaid with differences in protein-specific responses between individual animals. Our results provide a first, indepth look at the T cell repertoire in response to influenza infection and suggest that there is considerable heterogeneity at the MHC locus, which is akin to that in humans and an area of intense research interest.

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Cutting Edge: CD4 T Cells Generated from Encounter with Seasonal Influenza Viruses and Vaccines Have Broad Protein Specificity and Can Directly Recognize Naturally Generated Epitopes Derived from the Live Pandemic H1N1 Virus

Cited by 72 publications

References 18 publications

Infection with Seasonal Influenza Virus Elicits CD4 T Cells Specific for Genetically Conserved Epitopes That Can Be Rapidly Mobilized for Protective Immunity to Pandemic H1N1 Influenza Virus

Infection with Seasonal Influenza Virus Elicits CD4 T Cells Specific for Genetically Conserved Epitopes That Can Be Rapidly Mobilized for Protective Immunity to Pandemic H1N1 Influenza Virus

Cross-protective immunity against influenza pH1N1 2009 viruses induced by seasonal influenza A (H3N2) virus is mediated by virus-specific T-cells

Flow Cytometric and Cytokine ELISpot Approaches To Characterize the Cell-Mediated Immune Response in Ferrets following Influenza Virus Infection

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