A call to cellular &amp; humoral arms: Enlisting cognate T cell help to develop broad-spectrum vaccines against influenza A

McMurry, Julie A.; Johansson, Bert E.; Groot, Anne S. De

doi:10.4161/hv.4.2.5169

Cited by 42 publications

(34 citation statements)

References 126 publications

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“…If true, then the implications for heterosubtypic immunity are profound. Because of the high degree of genetic drift within influenza viruses (6,8,22,24,31,34,36), intermittent encounters with influenza virus strains in humans may preferentially boost T cells that are specific for conserved peptides enriched in nucleoprotein and polymerase proteins (2,7,22,23,30,43,56,82). However, if these CD4 T cells have limited contributions in facilitating antibody responses, they may not be particularly valuable for protection.…”

Section: Discussionmentioning

confidence: 99%

Infection of HLA-DR1 Transgenic Mice with a Human Isolate of Influenza A Virus (H1N1) Primes a Diverse CD4 T-Cell Repertoire That Includes CD4 T Cells with Heterosubtypic Cross-Reactivity to Avian (H5N1) Influenza Virus

Richards

Chaves

Sant

2009

J Virol

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The specificity of the CD4 T-cell immune response to influenza virus is influenced by the genetic complexity of the virus and periodic encounters with variant subtypes and strains. In order to understand what controls CD4 T-cell reactivity to influenza virus proteins and how the influenza virus-specific memory compartment is shaped over time, it is first necessary to understand the diversity of the primary CD4 T-cell response. In the study reported here, we have used an unbiased approach to evaluate the peptide specificity of CD4 T cells elicited after live influenza virus infection. We have focused on four viral proteins that have distinct intracellular distributions in infected cells, hemagglutinin (HA), neuraminidase (NA), nucleoprotein, and the NS1 protein, which is expressed in infected cells but excluded from virion particles. Our studies revealed an extensive diversity of influenza virus-specific CD4 T cells that includes T cells for each viral protein and for the unexpected immunogenicity of the NS1 protein. Due to the recent concern about pandemic avian influenza virus and because CD4 T cells specific for HA and NA may be particularly useful for promoting the production of neutralizing antibody to influenza virus, we have also evaluated the ability of HA-and NA-specific CD4 T cells elicited by a circulating H1N1 strain to cross-react with related sequences found in an avian H5N1 virus and find substantial cross-reactivity, suggesting that seasonal vaccines may help promote protection against avian influenza virus.In recent decades, investigators studying both murine and human T-cell responses to influenza virus have succeeded in identifying peptide epitopes from immunized or vaccinated individuals that are the targets of CD4 T cells. These studies suggest a considerable diversity in CD4 responses. Epitopes derived from hemagglutinin (HA), neuraminidase (NA), nuclear protein (NP), polymerase (PB1 and PB2), matrix (M1), and nonstructural protein (NS1) have all been identified (9, 19, 25-28, 32, 61, 64, 85, 86). Our own laboratory previously analyzed the peptide specificity of CD4 T cells in the primary response of HLA-DR1 transgenic mice toward a human isolate of influenza virus and found that the CD4 T-cell repertoire specific for HA alone was diverse and encompassed at least 30 different peptide epitopes (63). In general, studies with humans have been much less systematic than those with the mouse because of the difficulty in obtaining lymphocyte samples from recently infected individuals and because of the complexity of major histocompatibility complex (MHC) molecules expressed in humans. However, recent studies with MHC class II tetramer reagents (19,61,64,72,86) have permitted the visualization of CD4 T cells specific for influenza virus directly ex vivo or after a brief (10-to 14-day) in vitro expansion. Those studies have led to the conclusion that the repertoire of CD4 T cells is more diverse than that of CD8 T cells and that CD4 T cells that are specific for most influenza virus proteins can be ...

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Section: Discussionmentioning

confidence: 99%

Infection of HLA-DR1 Transgenic Mice with a Human Isolate of Influenza A Virus (H1N1) Primes a Diverse CD4 T-Cell Repertoire That Includes CD4 T Cells with Heterosubtypic Cross-Reactivity to Avian (H5N1) Influenza Virus

Richards

Chaves

Sant

2009

J Virol

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“…First, new antigens can be added to the HA. These include defined amounts of neuraminidase; M2e, a protein from the virus that elicits broad neutralization (82); conserved epitopes, including the newly described conserved fusion peptide in the stem of H1 and H5 HA (9,32,49,78,111); bivalent peptide conjugate that also may give broad protection (4); nucleoprotein that generates cellular immune responses; and (14,49). New formulations of influenza vaccine that could improve immunity are those employing DNA plasmids coding for HA, VLPs, nanoparticles with liposomes, and HA to which new adjuvants have been added using either oil in water or TLR ligands (125).…”

Section: Concluding Thoughtsmentioning

confidence: 99%

Vaccines: the Fourth Century

Plotkin

2009

Clin Vaccine Immunol

210

159

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Vaccine development, which began with Edward Jenner's observations in the late 18th century, has entered its 4th century. From its beginnings, with the use of whole organisms that had been weakened or inactivated, to the modern-day use of genetic engineering, it has taken advantage of the tools discovered in other branches of microbiology. Numerous successful vaccines are in use, but the list of diseases for which vaccines do not exist is long. However, the multiplicity of strategies now available, discussed in this article, portends even more successful development of vaccines.

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“…In recent years, influenza virus has been associated with around 40,000 underlying respiratory and circulatory deaths, and around 290,000 pneumonia and circulatory hospitalizations in the United States annually, with a disproportionate burden of disease in children and the elderly (60,61). This continued high burden of disease despite the availability of an effective vaccine may be in part due to the need for yearly redesign and manufacture of the vaccine, with resulting lower-than-optimal vaccination rates (3), and a yearly risk of mismatch between the vaccination and circulating strains (19,40). The recent human pandemic with a novel strain of H1N1 influenza, for which there is apparently little preexisting antibody-mediated immunity in the majority of humans, has accelerated the interest in production of vaccines that elicit a broadly cross-protective immune response (4,17,26,45).…”

mentioning

confidence: 99%

“…Once intracellular infection is established, immune control and clearance largely depend on the detection and elimination of infected host cells by the adaptive immune response (19,35,58). Cytotoxic CD8 T cells home to respiratory sites where virus replication is localized and eliminate infected cells (18,19,31,35,40,58,59). Antigen-specific B cells secrete neutralizing antibodies to HA and NA, which provide the most significant source of protection from future infections (18,19,31,35,40,58,59).…”

mentioning

confidence: 99%

Analyses of the Specificity of CD4 T Cells During the Primary Immune Response to Influenza Virus Reveals Dramatic MHC-Linked Asymmetries in Reactivity to Individual Viral Proteins

et al. 2010

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Influenza is a contagious, acute respiratory disease that is a major cause of morbidity and mortality throughout the world. CD4 T cells play an important role in the immune response to this pathogen through the secretion of antiviral cytokines, and by providing help to CD8 T cells and B cells to promote the development of immunological memory and neutralizing antibody responses. Despite these well-defined roles in the anti-influenza response, our understanding of CD4 T-cell diversity and specificity remains limited. In the study reported here, overlapping peptides representing 5 different influenza viral proteins were used in EliSpot assays to enumerate and identify the specificity of anti-influenza CD4 T cells directly ex vivo following infection of mice with influenza virus, using two strains that express unrelated MHC class II molecules. These experiments evaluated whether the reactivity of CD4 T cells generally tracked with particular influenza proteins, or whether MHC preferences were the predominant factor dictating anti-CD4 T-cell specificity in the primary immune response. We made the unexpected discovery that the distribution of CD4 T-cell specificities for different influenza proteins varied significantly depending on the single class II molecule expressed in vivo. In SJL mice, the majority of epitopes were specific for the HA protein, while the NP protein dominated the response in C57BL=10 mice. Given the diversity of human MHC class II molecules, these findings have important implications for the ability to rationally design a vaccine that will generate a specific CD4 T-cell immune response that is effective across diverse human populations.

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A call to cellular & humoral arms: Enlisting cognate T cell help to develop broad-spectrum vaccines against influenza A

Cited by 42 publications

References 126 publications

Infection of HLA-DR1 Transgenic Mice with a Human Isolate of Influenza A Virus (H1N1) Primes a Diverse CD4 T-Cell Repertoire That Includes CD4 T Cells with Heterosubtypic Cross-Reactivity to Avian (H5N1) Influenza Virus

Infection of HLA-DR1 Transgenic Mice with a Human Isolate of Influenza A Virus (H1N1) Primes a Diverse CD4 T-Cell Repertoire That Includes CD4 T Cells with Heterosubtypic Cross-Reactivity to Avian (H5N1) Influenza Virus

Vaccines: the Fourth Century

Analyses of the Specificity of CD4 T Cells During the Primary Immune Response to Influenza Virus Reveals Dramatic MHC-Linked Asymmetries in Reactivity to Individual Viral Proteins

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