The Dynamics of T-Cell Receptor Repertoire Diversity Following Thymus Transplantation for DiGeorge Anomaly

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dc.contributor.authorCiupe, Stanca M.en
dc.contributor.authorDevlin, Blythe H.en
dc.contributor.authorMarkert, Mary L.en
dc.contributor.authorKepler, Thomas B.en
dc.contributor.departmentMathematicsen
dc.date.accessioned2017-01-22T01:56:15Zen
dc.date.available2017-01-22T01:56:15Zen
dc.date.issued2009-06-01en
dc.description.abstractT cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after thymus transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective roles of TCR-specific vs. TCR-nonspecific regulatory signals in the growth of these emerging T-cell populations. During the course of the study, we measured peripheral blood T-cell concentrations, TCRβ V gene-segment usage and CDR3- length spectratypes over two years or more for each of the subjects. We find, through statistical analysis based on a novel stochastic population-dynamic T-cell model, that the carrying capacity corresponding to TCR-specific resources is approximately 1000-fold larger than that of TCR-nonspecific resources, implying that the size of the peripheral T-cell pool at steady state is determined almost entirely by TCR-nonspecific mechanisms. Nevertheless, the diversity of the TCR repertoire depends crucially on TCR-specific regulation. The estimated strength of this TCR-specific regulation is sufficient to ensure rapid establishment of TCR repertoire diversity in the early phase of T cell population growth, and to maintain TCR repertoire diversity in the face of substantial clonal expansion-induced perturbation from the steady state.en
dc.description.versionPublished versionen
dc.format.extent13 pagesen
dc.identifier.doihttps://doi.org/10.1371/journal.pcbi.1000396en
dc.identifier.issn1553-734Xen
dc.identifier.issue6en
dc.identifier.urihttp://hdl.handle.net/10919/74401en
dc.identifier.volume5en
dc.language.isoenen
dc.publisherPLOSen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000268436100005&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectBiochemical Research Methodsen
dc.subjectMathematical & Computational Biologyen
dc.subjectBiochemistry & Molecular Biologyen
dc.subjectSEVERE COMBINED IMMUNODEFICIENCYen
dc.subjectHOMEOSTATIC PROLIFERATIONen
dc.subjectIN-VIVOen
dc.subjectNAIVEen
dc.subjectCOMPETITIONen
dc.subjectSURVIVALen
dc.subjectSELECTIONen
dc.subjectIL-7en
dc.subjectINTERLEUKIN-7en
dc.subjectLYMPHOCYTESen
dc.titleThe Dynamics of T-Cell Receptor Repertoire Diversity Following Thymus Transplantation for DiGeorge Anomalyen
dc.title.serialPLOS Computational Biologyen
dc.typeArticle - Refereeden
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Scienceen
pubs.organisational-group/Virginia Tech/Science/COS T&R Facultyen
pubs.organisational-group/Virginia Tech/Science/Mathematicsen

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