title: pMHC affinity controls duration of CD8+ T cell-DC interactions and imprints timing of effector differentiation versus expansion.
abstract: 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.
authors: Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
authors: Aleksandra J
authors: 0000-0003-3138-3238
authors: AJ
authors: Ozga
authors: Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
authors: Federica
authors: 0000-0002-8426-2571
authors: F
authors: Moalli
authors: Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
authors: Jun
authors: 0000-0001-7511-4502
authors: J
authors: Abe
authors: 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.
authors: Jim
authors: 0000-0003-3805-0073
authors: J
authors: Swoger
authors: 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.
authors: James
authors: J
authors: Sharpe
authors: 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.
authors: Dietmar
authors: D
authors: Zehn
authors: Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
authors: Mario
authors: M
authors: Kreutzfeldt
authors: Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
authors: Doron
authors: 0000-0002-0247-2007
authors: D
authors: Merkler
authors: 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.
authors: Jorge
authors: 0000-0001-8856-7738
authors: J
authors: Ripoll
authors: Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland jstein@tki.unibe.ch.
authors: Jens V
authors: JV
authors: Stein
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D045142:Cross-Priming / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology*; D005786:Gene Expression Regulation; D053804:Granzymes / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D037181:Lectins, C-Type / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D042601:Lymphatic Vessels / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D014777:Virus Diseases / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D053804:Granzymes; D037181:Lectins, C-Type; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D000099192:CD69 Antigens