The intercell dynamics of T cells and dendritic cells in a lymph node-on-a-chip flow device

Abstract

T cells play a central role in immunity towards cancer and infectious diseases. T cell responses are initiated in the T cell zone of the lymph node (LN), where resident antigen-bearing dendritic cells (DCs) prime and activate antigen-specific T cells passing by. In the present study, we investigated the T cell : DC interaction in a microfluidic device to understand the intercellular dynamics and physiological conditions in the LN. We show random migration of antigen-specific T cells onto the antigen-presenting DC monolayer independent of the flow direction with a mean T cell : DC dwell time of 12.8 min and a mean velocity of 6 μm min⁻¹. Furthermore, we investigated the antigen specific vs. unspecific attachment and detachment of CD8⁺ and CD4⁺ T cells to DCs under varying shear stress. In our system, CD4⁺ T cells showed long stable contacts with APCs, whereas CD8⁺ T cells presented transient interactions with DCs. By varying the shear stress from 0.01 to 100 Dyn cm⁻², it was also evident that there was a much stronger attachment of antigen-specific than unspecific T cells to stationary DCs up to 1–12 Dyn cm⁻². The mechanical force of the cell : cell interaction associated with the pMHC–TCR match under controlled tangential shear force was estimated to be in the range of 0.25–4.8 nN. Finally, upon performing attachment & detachment tests, there was a steady accumulation of antigen specific CD8⁺ T cells and CD4⁺ T cells on DCs at low shear stresses, which were released at a stress of 12 Dyn cm⁻². This microphysiological model provides new possibilities to recreate a controlled mechanical force threshold of pMHC–TCR binding, allowing the investigation of intercellular signalling of immune synapses and therapeutic targets for immunotherapy.