(515bs) Role Of Mechanical Environment On Chemokine Signaling In Lymphocyte Homing

Dendritic cells (DCs) are potent antigen-presenting cells that play a vital role in both immunity and tolerance. Upon antigen uptake in peripheral tissues, they traffic into lymphatic vessels that transport them to regional lymph nodes where they deliver appropriate signals to T-cells to drive their proliferation and differentiation. Upregulation of the chemokine receptor CCR7 is critical for this trafficking, but the extent to which paracrine or autocrine signaling mechanisms underlie this process is unknown, since both DCs and lymphatic endothelium secrete CCR7 ligands. There exists small interstitial flows into lymphatics, and we demonstrate how this flow can be utilized to amplify directed chemokine gradients to lead DCs towards the lymphatic, specifically by creating autologous transcellular gradients of CCR7 ligands that drive chemotaxis in the flow direction. In an in vitro 3D model of cell migration under static conditions, lymphatic endothelium induced CCR7-dependent chemotaxis of mature mouse and human DCs. However, in the presence of interstitial flow, robust increases in CCR7-dependent directional migration occurred in a manner that was lymphatic endothelium-independent. Computational modeling estimated that small transcellular gradients of CCR7 ligand were created under flow to drive this response, and also showed that paracrine signaling (from the lymphatics) and autocrine signaling (from DCs) could be synergistic under flow. This work illustrates how activated DCs may be guided toward functional draining lymphatics to inititate an immune response.