A virtual lymph node model to dissect the requirements for T-cell activation by synapses and kinapses

Immunol Cell Biol. 2016 Aug;94(7):680-8. doi: 10.1038/icb.2016.36. Epub 2016 May 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / immunology
  • Antigens / metabolism
  • Cell Communication / immunology*
  • Cell Count
  • Cell Proliferation
  • Dendritic Cells / cytology
  • Immunological Synapses / metabolism*
  • Lymph Nodes / immunology*
  • Lymphocyte Activation / immunology*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological*
  • Peptides / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*

Substances

  • Antigens
  • Peptides