Multipronged <scp>CD</scp>4<sup>+</sup> T‐cell effector and memory responses cooperate to provide potent immunity against respiratory virus

Strutt, Tara M.; McKinstry, K. Kai; Marshall, Nikki B.; Vong, Allen M.; Dutton, Richard; Swain, Susan L.

doi:10.1111/imr.12088

Cited by 73 publications

(82 citation statements)

References 109 publications

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“…For example, in a recent human challenge model with H3N2 or H1N1 viruses, it was noted that that preexisting CD4 T cells specific for matrix or NP correlated best with lower virus shedding and disease. These cells also possess cytotoxic activity (25), which is also thought to be a key effector activity of CD4 T cells (50,84,85). The reagents and methods defined here will allow us to better probe links between specificity and function in ferrets.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Protective correlates include CD4 + and CD8 + memory T cells, IFNγ expressing and cytotoxic in both cases (130, 131). Mouse models reveal similar heterotypic protection and activities from CD4 + and CD8 + cells during influenza pneumonia (119, 132). Thus, naturally acquired heterotypic immune responses substantially limit the severity of respiratory infection by new strains of influenza virus.…”

Section: Remodeling: Responses To Lung Infection Differ Throughout a mentioning

confidence: 99%

Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

Quinton

Mizgerd

2015

Annu. Rev. Physiol.

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Pneumonia is initiated by microbes in the lung, but physiological processes integrating responses across diverse cell types and organ systems dictate the outcome of respiratory infection. Resistance, or actions of the host to eradicate living microbes, in the lungs involves a combination of innate and adaptive immune responses triggered by air-space infection. Resilience, or the ability of the host tissues to withstand the physiologically damaging effects of microbial and immune activities, is equally complex, precisely regulated, and determinative. Both immune resistance and tissue resilience are dynamic and change throughout the lifetime, but we are only beginning to understand such remodeling and how it contributes to the incidence of severe pneumonias, which diminishes as childhood progresses and then increases again among the elderly. Here, we review the concepts of resistance, resilience, and remodeling as they apply to pneumonia, highlighting recent advances and current significant knowledge gaps.

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“…21 Ideally, immunization with vaccines should induce a robust cytokine response on reencountering specific antigens. We did not find significant changes in cytokine production in response to the pandemic influenza antigens during the three months of study in both study groups.…”

Section: Discussionmentioning

confidence: 99%

Low expression of activation marker CD69 and chemokine receptors CCR5 and CXCR3 on memory T cells after 2009 H₁N₁influenza A antigen stimulation in vitro following H1N1 vaccination of HIV-infected individuals

Chawansuntati

Chotirosniramit

Sugandhavesa³

et al. 2015

Human Vaccines & Immunotherapeutics

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Unlike well-studied antibody responses to pandemic 2009 H1N1 influenza A virus vaccines in human immunodeficiency virus-infected (HIV+) individuals, less well understood are cell-mediated immune (CMI) responses to this antigen in this susceptible population. We investigated such influenza-specific CMI responses in 61 HIV+ individuals and in 20 HIV-negative (HIV-) healthy controls. Each was vaccinated with a single licensed dose of inactivated, split-virion vaccine comprised of the influenza A/California/7/2009 (H1N1) virus-like strain. Cells collected just prior to vaccination and at 1 and 3 months afterwards were stimulated in vitro with dialyzed vaccine antigen and assayed by flow cytometry for cytokines TNF-α, IFN-γ, IL-2, and IL-10, for degranulation marker CD107a, as well as phenotypes of memory T-cell subpopulations. Comparable increases of cytokine-producing and CD107a-expressing T cells were observed in both HIV+ subjects and healthy HIV-controls. However, by 3 months post-vaccination, in vitro antigen stimulation of peripheral blood mononuclear cells induced greater expansion in controls of both CD4 and CD8 central memory and effector memory T cells, as well as higher expression of the activation marker CD69 and chemokine receptors CCR5 and CXCR3 than in HIV+ subjects. We concluded CD4+ and CD8+ memory T cells produce cytokines at comparable levels in both groups, whereas the expression after in vitro stimulation of molecules critical for cell migration to infection sites are lower in the HIV+ than in comparable controls. Further immunization strategies against influenza are needed to improve the CMI responses in people living with HIV.

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Multipronged CD4⁺ T‐cell effector and memory responses cooperate to provide potent immunity against respiratory virus

Cited by 73 publications

References 109 publications

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

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

Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

Low expression of activation marker CD69 and chemokine receptors CCR5 and CXCR3 on memory T cells after 2009 H₁N₁influenza A antigen stimulation in vitro following H1N1 vaccination of HIV-infected individuals

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Multipronged CD4+ T‐cell effector and memory responses cooperate to provide potent immunity against respiratory virus

Cited by 73 publications

References 109 publications

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

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

Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

Low expression of activation marker CD69 and chemokine receptors CCR5 and CXCR3 on memory T cells after 2009 H1N1influenza A antigen stimulation in vitro following H1N1 vaccination of HIV-infected individuals

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Product

Resources

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Multipronged CD4⁺ T‐cell effector and memory responses cooperate to provide potent immunity against respiratory virus

Low expression of activation marker CD69 and chemokine receptors CCR5 and CXCR3 on memory T cells after 2009 H₁N₁influenza A antigen stimulation in vitro following H1N1 vaccination of HIV-infected individuals