title: A virtual lymph node model to dissect the requirements for T-cell activation by synapses and kinapses.
abstract: The initiation of T-cell responses in lymph nodes requires T cells to integrate signals delivered by dendritic cells (DCs) during long-lasting contacts (synapses) or more transient interactions (kinapses). However, it remains extremely challenging to understand how a specific sequence of contacts established by T cells ultimately dictates T-cell fate. Here, we have coupled a computational model of T-cell migration and interactions with DCs with a real-time, flow cytometry-like representation of T-cell activation. In this model, low-affinity peptides trigger T-cell proliferation through kinapses but we show that this process is only effective under conditions of high DC densities and prolonged antigen availability. By contrast, high-affinity peptides favor synapse formation and a vigorous proliferation under a wide range of antigen presentation conditions. In line with the predictions, decreasing the DC density in vivo selectively abolished proliferation induced by the low-affinity peptide. Finally, our results suggest that T cells possess a biochemical memory of previous stimulations of at least 1-2 days. We propose that the stability of T-cell-DC interactions, apart from their signaling potency, profoundly influences the robustness of T-cell activation. By offering the ability to control parameters that are difficult to manipulate experimentally, the virtual lymph node model provides new possibilities to tackle the fundamental mechanisms that regulate T-cell responses elicited by infections or vaccines.
authors.affiliation: Institut Pasteur, Dynamics of Immune Responses Unit, Paris, France.|INSERM U1223, Paris, France.
authors.forename: Hélène D
authors.initials: HD
authors.lastname: Moreau
authors.affiliation: Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.
authors.forename: Gib
authors.initials: G
authors.lastname: Bogle
authors.affiliation: Institut Pasteur, Dynamics of Immune Responses Unit, Paris, France.|INSERM U1223, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bousso
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000941:Antigens / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology*; D002452:Cell Count; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology; D054992:Immunological Synapses / Q000378:metabolism*; D008198:Lymph Nodes / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010455:Peptides / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D000941:Antigens; D010455:Peptides