pMHC affinity controls duration of CD8+ T cell&-DCinteractions and imprints timing of effector differentiationversus expansion

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dc.contributor.author Ozga, Aleksandra J.
dc.contributor.author Moalli, Federica
dc.contributor.author Abe, Jun
dc.contributor.author Swoger, Jim
dc.contributor.author Sharpe, James
dc.contributor.author Zhen, Dietmar
dc.contributor.author Kreutzfeldt, Mario
dc.contributor.author Merkler, Doron
dc.contributor.author Ripoll Lorenzo, Jorge
dc.contributor.author Stein, Jens V.
dc.date.accessioned 2016-12-13T11:16:12Z
dc.date.available 2017-04-01T22:00:08Z
dc.date.issued 2016-10-31
dc.identifier.bibliographicCitation The journal of experimental medicine, 2016, 213 (12), p. 2811
dc.identifier.issn 0022-1007
dc.identifier.uri http://hdl.handle.net/10016/23947
dc.description.abstract During adaptive immune responses, CD8+ T cells with low TCR affinities are released early into the circulation before high-affinityclones become dominant at later time points. How functional avidity maturation is orchestrated in lymphoid tissue andhow low-affinity cells contribute to host protection remains unclear. In this study, we used intravital imaging of reactive lymphnodes (LNs) to show that T cells rapidly attached to dendritic cells irrespective of TCR affinity, whereas one day later, theduration of these stable interactions ceased progressively with lowering peptide major histocompatibility complex (pMHC)affinity. This correlated inversely BATF (basic leucine zipper transcription factor, ATF-like) and IRF4 (interferon-regulatedfactor 4) induction and timing of effector differentiation, as low affinity&-primed T cells acquired cytotoxic activity earlierthan high affinity&-primed ones. After activation, low-affinity effector CD8+ T cells accumulated at efferent lymphatic vesselsfor egress, whereas high affinity&-stimulated CD8+ T cells moved to interfollicular regions in a CXCR3-dependent manner forsustained pMHC stimulation and prolonged expansion. The early release of low-affinity effector T cells led to rapid target cellelimination outside reactive LNs. Our data provide a model for affinity-dependent spatiotemporal orchestration of CD8+ T cellactivation inside LNs leading to functional avidity maturation and uncover a role for low-affinity effector T cells during earlymicrobial containment.
dc.description.sponsorship This work was supported by a Novartis Research grant (to A.J. Ozga) and Swiss National Science Foundation grants (31003A_135649 and CR23I3_156234 to J.V. Stein and CRS II3_141918 to J.V. Stein and J. Sharpe). J. Ripoll acknowledges support from European Commission FP7 Career Integration Grants (HIGH-THROUGHPUT TOMO), European Commission FP7 Marie Curie Actions (grant 2PM), and the Ministerio de Economía y Competitividad (grant FIS2013-41802-R). J. Sharpe acknowledges support from the Ministerio de Economía y Competitividad, Centro de Excelencia Severo Ochoa 2013–2017 (grant SEV-2012-0208).
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher The Rockefeller University Press
dc.rights © The Autors, 2016
dc.rights Atribución-NoComercial-SinDerivadas 3.0 España
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/es/
dc.title pMHC affinity controls duration of CD8+ T cell&-DCinteractions and imprints timing of effector differentiationversus expansion
dc.type article
dc.subject.eciencia Biología y Biomedicina
dc.subject.eciencia Ingeniería Mecánica
dc.identifier.doi https://doi.org/10.1084/jem.20160206
dc.rights.accessRights openAccess
dc.relation.projectID Gobierno de España. FIS-2013-41802-R
dc.relation.projectID Gobierno de España. SEV-2012-0208
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/333632
dc.type.version publishedVersion
dc.identifier.publicationissue 12
dc.identifier.publicationtitle The Journal of Experimental Medicine
dc.identifier.publicationvolume 213
dc.identifier.uxxi AR/0000018403
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