Sponsor:
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).
Project:
Gobierno de España. FIS-2013-41802-R Gobierno de España. SEV-2012-0208 info:eu-repo/grantAgreement/EC/FP7/333632
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-affiDuring 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.[+][-]