Neonatal CD8 T-cell Hierarchy Is Distinct from Adults and Is Influenced by Intrinsic T cell Properties in Respiratory Syncytial Virus Infected Mice

Ruckwardt, Tracy J.; Malloy, Allison M. W.; Gostick, Emma; Price, David A.; Dash, Pradyot; McClaren, Jennifer; Thomas, Paul G.; Graham, Barney S.

doi:10.1371/journal.ppat.1002377

Cited by 72 publications

(93 citation statements)

References 51 publications

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“…Recently, however, our work and that of others has shown a disconnect between naïve CTLp frequency and immune magnitudes (18,40) which, in our study, resulted from incomplete recruitment and/or expansion of T-cell populations after antigen challenge. Given that T-cell precursor recruitment and expansion is not necessarily uniform following antigen challenge (even where relative precursor frequencies and immune magnitudes correlate, the relationship is rarely absolute), the current study sought to elucidate how naïve CTLp repertoires influence corresponding immune repertoires after influenza virus infection.…”

Section: Studies That Have Directly Enumerated Naïve Cd4contrasting

confidence: 62%

Ecological analysis of antigen-specific CTL repertoires defines the relationship between naïve and immune T-cell populations

Thomas

Handel

Doherty

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Ecology is typically thought of as the study of interactions organisms have with each other and their environment and is focused on the distribution and abundance of organisms both within and between environments. On a molecular level, the capacity to probe analogous questions in the field of T-cell immunology is imperative as we acquire substantial datasets both on epitope-specific T-cell populations through high-resolution analyses of T-cell receptor (TCR) use and on global T-cell populations analyzed via high-throughput DNA sequencing. Here, we present the innovative application of existing statistical measures (used typically in the field of ecology), together with unique statistical analyses, to comprehensively assess how the naïve epitope-specific CD8 + cytotoxic T lymphocyte (CTL) repertoire translates to that found following an influenza-virus-specific immune response. Such interrogation of our extensive, cumulated TCR CDR3β sequence datasets, derived from both naïve and immune 114 , and influenza nonstructural protein 2 amino acid residues 114-121), demonstrates that epitope-specific TCR use in an antiviral immune response is the consequence of a complex interplay between the intrinsic characteristics of the naïve cytotoxic T lymphocyte precursor pool and extrinsic (likely antigen driven) influences, the contribution of which varies in an epitopespecific fashion.+ cytotoxic T lymphocytes (CTLs), the clonotypic T-cell receptor (TCR) recognizes "nonself" peptides (p) in complex with "self" class I MHC glycoproteins (MHCI). To recognize and respond to the vast array of novel pMHCI determinants encountered by a given individual (or population), the adaptive immune system uses the recombination of variable (V), junctional (J), diversity (D), and constant (C) somatic gene segments to establish an extraordinary spectrum of TCRs. Most of the observed TCR diversity results from imprecise joining of these gene segments and the addition of nontemplate-encoded nucleotides at V(D)J junctions (1). The consequence is that TCR diversity is principally a function of the CDR3 regions, meaning that clonal uniqueness is reliably defined by the TCRαβ CDR3 sequences.The nature of the highly specific TCR-pMHC recognition event likely determines functional outcomes after T-cell activation (2-6). Thus, the complexity and distribution of TCR use within a responding CTL population is likely to have a very real impact on the efficacy of T-cell-mediated pathogen clearance. Certainly, both virus control and the prevention of mutational escape operate more effectively if the host response is characterized by a diverse, rather than a limited, spectrum of pMHCI-specific TCRs (7-12). Further, TCR diversity has also been associated with effective cross-reactive immunity against different virus infections (13).Single cell RT-PCR analysis of CDR3 nucleotide sequences has provided an unprecedented level of resolution for characterizing TCR use, especially in the case of CTL responses to pathogens. Such detailed dissection of epitope-speci...

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Section: Studies That Have Directly Enumerated Naïve Cd4contrasting

confidence: 62%

Ecological analysis of antigen-specific CTL repertoires defines the relationship between naïve and immune T-cell populations

Thomas

Handel

Doherty

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…7C to E). Because IL-4R␣ levels are higher in neonates, where viral loads are lower than those in adults (30), and do not change in response to RSV infection (4), we also propose that the immunomodulatory aspects of IFN-␣ play a role in the effects observed here. Thus, we believe that both of the mechanisms of IFN-␣ action outlined above are involved in the observed protective effect.…”

Section: Discussionmentioning

confidence: 80%

Limited Type I Interferons and Plasmacytoid Dendritic Cells during Neonatal Respiratory Syncytial Virus Infection Permit Immunopathogenesis upon Reinfection

Cormier

Shrestha

Saravia

et al. 2014

J Virol

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Respiratory syncytial virus (RSV) infection is the number one cause of bronchiolitis in infants IMPORTANCE Respiratory syncytial virus (RSV) is the most significant cause of lower respiratory tract infection in infancy worldwide.Despite the dire need, we have failed to produce efficacious RSV vaccines or therapeutics. Part of the reason for this failure is our lack of understanding of how RSV interacts with the infant immune system to suppress the development of protective immunity. In the study described in the present paper, we used a neonatal mouse model, which more closely mimics human infants, to study the role of the innate immune system, particularly type I interferons (IFNs) and plasmacytoid dendritic cells (pDCs), in the pathogenesis of RSV infection. RSV infection in neonates induced limited type I IFN and pDC responses. IFN-␣ treatment or adoptive transfer of adult pDCs capable of producing IFN-␣ prior to neonatal RSV infection decreased Th2-biased immunopathogenesis during reinfection. These data suggest that IFN-␣ is a promising target for future RSV vaccine design.

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“…Further, T cells in neonates have been reported to be impaired with regard to migration to the lung following infection (17). The combined deficiencies in DC maturation and T cell responsiveness are likely major contributors to the impaired T cell responses observed in vivo following infection or vaccination (11,(18)(19)(20). In addition to decreased responsiveness, data suggest a Th2 bias in the neonate (7).…”

mentioning

confidence: 99%

Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates

Kim

Holbrook

Hayward

et al. 2015

J Virol

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Influenza virus can cause life-threatening infections in neonates and young infants. Although vaccination is a major countermeasure against influenza, current vaccines are not approved for use in infants less than 6 months of age, in part due to the weak immune response following vaccination. Thus, there is a strong need to develop new vaccines with improved efficacy for this vulnerable population. To address this issue, we established a neonatal African green monkey (AGM) nonhuman primate model that could be used to identify effective influenza vaccine approaches for use in young infants. We assessed the ability of flagellin, a Toll-like receptor 5 (TLR5) agonist, to serve as an effective adjuvant in this at-risk population. Four-to 6-day-old AGMs were primed and boosted with inactivated PR8 influenza virus (IPR8) adjuvanted with either wild-type flagellin or inactive flagellin with a mutation at position 229 (m229), the latter of which is incapable of signaling through TLR5. Increased IgG responses were observed following a boost, as well as at early times after challenge, in infants vaccinated with flagellin-adjuvanted IPR8. Inclusion of flagellin during vaccination also resulted in a significantly increased number of influenza virus-specific T cells following challenge compared to the number in infants vaccinated with the m229 adjuvant. Finally, following challenge infants vaccinated with IPR8 plus flagellin exhibited a reduced pathology in the lungs compared to that in infants that received IPR8 plus m229. This study provides the first evidence of flagellin-mediated enhancement of vaccine responses in nonhuman primate neonates. Influenza virus remains one of the leading causes of morbidity and mortality worldwide. Infants less than 6 months of age are particularly vulnerable to development of severe disease following infection (1). Diseases associated with influenza virus infection in children include otitis media, pneumonia, myositis, and croup. While oseltamivir (Tamiflu), one of the two FDA-approved antiinfluenza drugs, can be used in infants aged 2 weeks and older, concerns exist due to the potential for adverse effects, drug resistance, and limited effectiveness in young infants (2).Currently, there are three approved approaches for vaccination against influenza in the United States: intramuscular (i.m.) administration of inactivated influenza virus, intramuscular administration of recombinant hemagglutinin (HA) proteins, and intranasal administration of a live attenuated influenza virus (LAIV). The first is approved for use in individuals aged 6 months and older, the second for use in individuals aged 18 to 49 years, and the last for use in healthy individuals aged 2 to 49 years. Thus, none are approved for use in the vulnerable neonate population. While the lack of approval for the use of these vaccines in the very young may reflect some safety concerns, a principal factor is the poor immune responses elicited in human neonates (3,4).Previous studies, while limited, have shown that an initia...

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Neonatal CD8 T-cell Hierarchy Is Distinct from Adults and Is Influenced by Intrinsic T cell Properties in Respiratory Syncytial Virus Infected Mice

Cited by 72 publications

References 51 publications

Ecological analysis of antigen-specific CTL repertoires defines the relationship between naïve and immune T-cell populations

Ecological analysis of antigen-specific CTL repertoires defines the relationship between naïve and immune T-cell populations

Limited Type I Interferons and Plasmacytoid Dendritic Cells during Neonatal Respiratory Syncytial Virus Infection Permit Immunopathogenesis upon Reinfection

Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates

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