Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and small children. RSV infection in mice is characterized by significant immunopathology which is mediated by CD8+ cytotoxic T lymphocytes (CTL). Past studies have suggested that CD8+ T cells with different functional properties and characteristics can be elicited following infection or immunization, and may have differential effects on viral clearance and RSV-associated illness. We have described differences between neonatal and adult CD8+ T cell responses elicited during RSV infection. Differences in clonotype, functional avidity, and other intrinsic parameters of the CD8+ T cell response may help dictate the epitope hierarchy established following infection. We are currently evaluating lung dendritic cell responses, and the elicitation of adaptive responses in both neonates and adults. This work has been greatly aided within the last year by the development of three strains of transgenic mice with CD8+ T cells specific for RSV. Continued work on this study will fully characterize CD8+ T responses to RSV, elucidate important factors that dictate the type of CD8+ T cell response that is generated, and help understand how other cell types regulate the CD8+ T cell response to result in either a beneficial or a detrimental effect.

Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2012
Total Cost
$686,747
Indirect Cost
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Malloy, Allison M W; Ruckwardt, Tracy J; Morabito, Kaitlyn M et al. (2016) Pulmonary Dendritic Cell Subsets Shape the Respiratory Syncytial Virus-Specific CD8+ T Cell Immunodominance Hierarchy in Neonates. J Immunol :
Morabito, K M; Ruckwardt, T R; Redwood, A J et al. (2016) Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells in the lung. Mucosal Immunol :
Ruckwardt, Tracy J; Morabito, Kaitlyn M; Graham, Barney S (2016) Determinants of early life immune responses to RSV infection. Curr Opin Virol 16:151-7
Morabito, Kaitlyn M; Erez, Noam; Graham, Barney S et al. (2016) Phenotype and Hierarchy of Two Transgenic T Cell Lines Targeting the Respiratory Syncytial Virus KdM282-90 Epitope Is Transfer Dose-Dependent. PLoS One 11:e0146781
Pawlak, Joanna B; Gential, Geoffroy P P; Ruckwardt, Tracy J et al. (2015) Bioorthogonal deprotection on the dendritic cell surface for chemical control of antigen cross-presentation. Angew Chem Int Ed Engl 54:5628-31
Ruckwardt, Tracy J; Malloy, Allison M W; Morabito, Kaitlyn M et al. (2014) Quantitative and qualitative deficits in neonatal lung-migratory dendritic cells impact the generation of the CD8+ T cell response. PLoS Pathog 10:e1003934
Bar-Haim, Erez; Erez, Noam; Malloy, Allison M W et al. (2014) CD8+ TCR transgenic strains expressing public versus private TCR targeting the respiratory syncytial virus K(d)M2(82-90) epitope demonstrate similar functional profiles. PLoS One 9:e99249
Billam, Padma; Bonaparte, Kathryn L; Liu, Jie et al. (2011) T Cell receptor clonotype influences epitope hierarchy in the CD8+ T cell response to respiratory syncytial virus infection. J Biol Chem 286:4829-41
Ruckwardt, Tracy J; Malloy, Allison M W; Gostick, Emma et al. (2011) Neonatal CD8 T-cell hierarchy is distinct from adults and is influenced by intrinsic T cell properties in respiratory syncytial virus infected mice. PLoS Pathog 7:e1002377
Liu, Jie; Ruckwardt, Tracy J; Chen, Man et al. (2010) Epitope-Specific Regulatory CD4 T Cells Reduce Virus-Induced Illness while Preserving CD8 T-Cell Effector Function at the Site of Infection. J Virol 84:10501-9

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