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dc.contributor.authorRudolph, Mark E.
dc.contributor.authorMcArthur, Monica A.
dc.contributor.authorMagder, Laurence S.
dc.contributor.authorBarnes, Robin S.
dc.contributor.authorChen, Wilbur H.
dc.contributor.authorSztein, Marcelo B.
dc.creatorRudolph, M.
dc.date.accessioned2019-07-19T20:32:11Z
dc.date.available2019-07-19T20:32:11Z
dc.date.issued2019-01-01
dc.identifier.urihttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85063293829&origin=inward
dc.identifier.urihttp://hdl.handle.net/10713/10105
dc.description.abstractHuman-restricted Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever-a life-threatening disease of great global health significance, particularly in the developing world. Ty21a is an oral live-attenuated vaccine that protects against the development of typhoid disease in part by inducing robust T cell responses, among which multifunctional CD8+ cytotoxic T lymphocytes (CTL) play an important role. Following Ty21a vaccination, a significant component of adult CTL have shown to be targeted to S. Typhi antigen presented by the conserved major histocompatibility complex (MHC) class Ib molecule, human leukocyte antigen-E (HLA-E). S. Typhi challenge studies have shown that baseline, multifunctional HLA-E responsive T cells are associated with protection from, and delayed onset of, typhoid disease. However, despite the overwhelming burden of typhoid fever in school-aged children, and due to limited availability of pediatric samples, incomplete information is available regarding these important HLA-E-restricted responses in children, even though studies have shown that younger children may be less likely to develop protective cell mediated immune (CMI) responses than adults following vaccination. To address this gap, we have studied this phenomenon in depth by using mass cytometry to analyze pediatric and adult T cell responses to HLA-E-restricted S. Typhi antigen presentation, before and after Ty21a vaccination. Herein, we show variable responses in all age strata following vaccination among T effector memory (TEM) and T effector memory CD45RA+ (TEMRA) cells based on conventional gating analysis. However, by utilizing the dimensionality reduction tool tSNE (t-distributed Stochastic Neighbor Embedding), we are able to identify diverse, highly multifunctional gut-homing- TEM and TEMRA clusters of cells which are more abundant in adult and older pediatric participants than in younger children. These findings highlight a potential age-associated maturation of otherwise conserved HLA-E restricted T cell responses. Such insights, coupled with the marked importance of multifunctional T cell responses to combat infection, may better inform future pediatric vaccination strategies against S. Typhi and other infectious diseases. Copyright © 2019 the authors.en_US
dc.description.sponsorshipThis work was supported, in part, by NIAID, NI, DHHS federal research grants R01 AI036525, and U19 AI082655 [Cooperative Center for Human Immunology (CCHI)].en_US
dc.description.urihttps://www.doi.org/10.3389/fimmu.2019.00257en_US
dc.language.isoen_USen_US
dc.publisherFrontiers Media S.A.en_US
dc.relation.ispartofFrontiers in Immunologyen_US
dc.subjectDimensionality reductionen_US
dc.subjectHLA-E restricted responsesen_US
dc.subjectMultifunctionalityen_US
dc.subjectPediatric immunologyen_US
dc.subjectSalmonella typhien_US
dc.subjectT cell responseen_US
dc.subjectTy21aen_US
dc.subjectTyphoiden_US
dc.titleAge-associated heterogeneity of Ty21A-induced T cell responses to HLA-E restricted Salmonella typhi antigen presentationen_US
dc.typeArticleen_US
dc.identifier.doi10.3389/fimmu.2019.00257
dc.identifier.pmid30886613
dc.relation.volume10


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