CD4 T Cell Help Is Limiting and Selective during the Primary B Cell Response to Influenza Virus Infection

Alam, Shabnam; Knowlden, Zackery A. G.; Sangster, Mark Y.; Sant, Andrea J.

doi:10.1128/jvi.02077-13

Cited by 58 publications

(87 citation statements)

References 90 publications

(103 reference statements)

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“…The results have shown that populating a host with CD4 T cell memory cells enhances the germinal center (GC) and Ab responses to influenza virus infection, suggesting that CD4 T cell help is a limiting factor in the B cell response to infection. Analysis of serum Ab specific for HA and NP by ELISA showed that a match between CD4 T cell help and Ab specificity, as well as HA-specific CD4 T cell memory, are needed for accelerated Ab responses (35). These results suggested that efforts to promote CD4 T cell immunity specific for HA would likely enhance long-lived neutralizing Ab responses, as CD4 T cells help promote B cell affinity maturation to plasma cells and B cell memory cells.…”

Section: Influenza Vaccinesmentioning

confidence: 85%

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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Section: Influenza Vaccinesmentioning

confidence: 85%

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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“…Our laboratory (80) and others (81) have shown that there is a deterministic linkage in specificities for T and B lymphocytes in response to enveloped viruses. In a mouse model of influenza infection, we discovered that the magnitude and kinetics of the HA-specific B cell response were accelerated when the host was armed with memory HA-specific CD4 T cells but were not helped in the presence of NP-specific CD4 cells and vice versa (80). Also, in tracking expansion of human CD4 T cells after vaccination, we determined that the HA-specific response, rather than to those specific for M1 and NP, correlated best with the neutralizing antibody response (56).…”

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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“…Recent studies have shown that antigen specificity of CD4 + T cells responding to influenza vaccination is linked to neutralizing antibody responses. 34,46 Mice that develop CD4 + T cell memory to HA exhibit enhanced neutralizing antibody levels and lower lung viral titers in comparison with mice bearing nucleoprotein-specific CD4 + T cell memory. 47 Linked specificity is also observed in humans who receive inactivated virus vaccine, which contains internal proteins in addition to the critical antigen HA.…”

Section: Ha-specific Cd4+ T Cells Are Linked To Neutralizing Antibodymentioning

confidence: 99%

“…Monovalent pandemic H1N1 and H5N1 vaccination studies show that HI titers correlate with HA-specific CD4 + T cell expansion, but do not track with NP-specific CD4 + T cell levels. 34,46 Moreover, circulating Tfh in humans are predominantly HA-specific. 48 These studies suggest a vaccine strategy that boosts protective antibody responses via memory CD4 + T cell induction could rely on HA-derived epitopes, despite closer sequence identity between seasonal and avian influenza internal antigens.…”

Section: Ha-specific Cd4+ T Cells Are Linked To Neutralizing Antibodymentioning

confidence: 99%

T cell epitope engineering: an avian H7N9 influenza vaccine strategy for pandemic preparedness and response

Moise

Biron

Boyle

et al. 2018

Human Vaccines & Immunotherapeutics

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The delayed availability of vaccine during the 2009 H1N1 influenza pandemic created a sense of urgency to better prepare for the next influenza pandemic. Advancements in manufacturing technology, speed and capacity have been achieved but vaccine effectiveness remains a significant challenge. Here, we describe a novel vaccine design strategy called immune engineering in the context of H7N9 influenza vaccine development. The approach combines immunoinformatic and structure modeling methods to promote protective antibody responses against H7N9 hemagglutinin (HA) by engineering whole antigens to carry seasonal influenza HA memory CD4+ T cell epitopes – without perturbing native antigen structure – by galvanizing HA-specific memory helper T cells that support sustained antibody development against the native target HA. The premise for this vaccine concept rests on (i) the significance of CD4+ T cell memory to influenza immunity, (ii) the essential role CD4+ T cells play in development of neutralizing antibodies, (iii) linked specificity of HA-derived CD4+ T cell epitopes to antibody responses, (iv) the structural plasticity of HA and (v) an illustration of improved antibody response to a prototype engineered recombinant H7-HA vaccine. Immune engineering can be applied to development of vaccines against pandemic concerns, including avian influenza, as well as other difficult targets.

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CD4 T Cell Help Is Limiting and Selective during the Primary B Cell Response to Influenza Virus Infection

Cited by 58 publications

References 90 publications

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

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

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

T cell epitope engineering: an avian H7N9 influenza vaccine strategy for pandemic preparedness and response

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