The Role of CD4 T Cell Memory in Generating Protective Immunity to Novel and Potentially Pandemic Strains of Influenza

DiPiazza, Anthony; Richards, Katherine A.; Knowlden, Zackery A. G.; Nayak, Jennifer L.; Sant, Andrea J.

doi:10.3389/fimmu.2016.00010

Cited by 43 publications

(47 citation statements)

References 67 publications

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“…It is becoming increasingly clear that viral protein specificity may be a key determinant in the effector program of influenza virus-specific T cells (25,(61)(62)(63). However, due to a lack of ferret-specific reagents, measuring antigen-specific CD4 and CD8 T cell responses has not been possible.…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…This conclusion supports the model that the nature and complexity of the antigen taken up by antigen-specific B cells will determine the specificity of CD4 T cells that can provide help for expansion and production of high affinity antibodies. The abundance of these CD4 T cell specificities recruited into the response will likely provide the best correlate of protective antibody responses, with other viral antigen specificities either being neutral or negative (149). …”

Section: Provision Of Cd4 T Cell Help For B Cell Responses To Seasonamentioning

confidence: 99%

“…The abundance of these CD4 T cell specificities recruited into the response will likely provide the best correlate of protective antibody responses, with other viral antigen specificities either being neutral or negative. 149…”

Section: Analyses Of Human Responses To Avian Influenza Virus Vaccinesmentioning

confidence: 99%

CD4 T cells in protection from influenza virus: Viral antigen specificity and functional potential

Sant

DiPiazza

Nayak

et al. 2018

Immunological Reviews

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CD4 T cells convey a number of discrete functions to protective immunity to influenza, a complexity that distinguishes this arm of adaptive immunity from B cells and CD8 T cells. Although the most well recognized function of CD4 T cells is provision of help for antibody production, CD4 T cells are important in many aspects of protective immunity. Our studies have revealed that viral antigen specificity is a key determinant of CD4 T cell function, as illustrated both by mouse models of infection and human vaccine responses, a factor whose importance is due at least in part to events in viral antigen handling. We discuss research that has provided insight into the diverse viral epitope specificity of CD4 T cells elicited after infection, how this primary response is modified as CD4 T cells home to the lung, establish memory, and after challenge with a secondary and distinct influenza virus strain. Our studies in human subjects point out the challenges facing vaccine efforts to facilitate responses to novel and avian strains of influenza, as well as strategies that enhance the ability of CD4 T cells to promote protective antibody responses to both seasonal and potentially pandemic strains of influenza.

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“…Additional discussion focused on issues of CD4 T cell immunodominance and the nature of the Ag taken up by the HA-specific B cells after infection and vaccination. Also considered was that the contribution of CD4 T cells to the neutralizing Ab response may be either positive or negative, depending on the viral Ag specificity and the effector phenotype of the CD4 T cells (40). The discussion group suggested that the specific composition of administered influenza vaccines might have an important role in dictating long-term immunity.…”

Section: Influenza Vaccinesmentioning

confidence: 99%

Waning Immunity and Microbial Vaccines—Workshop of the National Institute of Allergy and Infectious Diseases

Plotkin

Edwards

et al. 2017

Clin Vaccine Immunol

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Since the middle of the 20th century, vaccines have made a significant public health impact by controlling infectious diseases globally. Although long-term protection has been achieved with some vaccines, immunity wanes over time with others, resulting in outbreaks or epidemics of infectious diseases. Long-term protection against infectious agents that have a complex life cycle and antigenic variation remains a key challenge. Novel strategies to characterize the short-and long-term immune responses to vaccines and to induce immune responses that mimic natural infection have recently emerged. New technologies and approaches in vaccinology, such as adjuvants, delivery systems, and antigen formulations, have the potential to elicit more durable protection and fewer adverse reactions; together with in vitro systems, these technologies have the capacity to model and accelerate vaccine development. The National Institute of Allergy and Infectious Diseases (NIAID) held a workshop on 19 September 2016 that focused on waning immunity to selected vaccines (for Bordetella pertussis, Salmonella enterica serovar Typhi, Neisseria meningitidis, influenza, mumps, and malaria), with an emphasis on identifying knowledge gaps, future research needs, and how this information can inform development of more effective vaccines for infectious diseases.

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The Role of CD4 T Cell Memory in Generating Protective Immunity to Novel and Potentially Pandemic Strains of Influenza

Cited by 43 publications

References 67 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

CD4 T cells in protection from influenza virus: Viral antigen specificity and functional potential

Waning Immunity and Microbial Vaccines—Workshop of the National Institute of Allergy and Infectious Diseases

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