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J Exp Med. 2016 Nov 14;213(12):2811-2829. Epub 2016 Oct 31.

pMHC affinity controls duration of CD8+ T cell-DC interactions and imprints timing of effector differentiation versus expansion.

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Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
Systems Biology Research Unit, European Molecular Biology Laboratory/Centre for Genomic Regulation, Barcelona Institute of Science and Technology, 08003 Barcelona, Spain.
Universitat Pompeu Fabra, 08002 Barcelona, Spain.
Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain.
Swiss Vaccine Research Institute, Centre des laboratoires d'Epalinges, 1066 Epalinges, Switzerland.
Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland.
Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
Department of Bioengineering and Aerospace Engineering, Universidad Carlos III of Madrid, 28911 Madrid, Spain.
Experimental Medicine and Surgery Unit, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, 28007 Madrid, Spain.
Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland


During adaptive immune responses, CD8+ T cells with low TCR affinities are released early into the circulation before high-affinity clones become dominant at later time points. How functional avidity maturation is orchestrated in lymphoid tissue and how low-affinity cells contribute to host protection remains unclear. In this study, we used intravital imaging of reactive lymph nodes (LNs) to show that T cells rapidly attached to dendritic cells irrespective of TCR affinity, whereas one day later, the duration 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-regulated factor 4) induction and timing of effector differentiation, as low affinity-primed T cells acquired cytotoxic activity earlier than high affinity-primed ones. After activation, low-affinity effector CD8+ T cells accumulated at efferent lymphatic vessels for egress, whereas high affinity-stimulated CD8+ T cells moved to interfollicular regions in a CXCR3-dependent manner for sustained pMHC stimulation and prolonged expansion. The early release of low-affinity effector T cells led to rapid target cell elimination outside reactive LNs. Our data provide a model for affinity-dependent spatiotemporal orchestration of CD8+ T cell activation inside LNs leading to functional avidity maturation and uncover a role for low-affinity effector T cells during early microbial containment.

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