Adaptive strategies of dendritic cell migration in response to environmental cues

Cell migration is a crucial process in animal development and maintenance. It is incredibly heterogeneous, with different cell types utilizing fundamentally distinct migration strategies. The strategies also depend on the cellular microenvironment, where cells can switch between migration modes as they encounter new environmental cues. In this thesis, we investigated how dendritic cells adapt their migration strategy when encountering geometrically, mechanically and chemically distinct environments. When dendritic cells are embedded in a homogeneous fibrous network, they migrate in a fast and directional amoeboid manner. In this migration strategy, extracellular proteolysis and integrin-mediated adhesions are dispensable. Instead, the cells use topography of the environment to propel their cell body forward. To migrate efficiently in the maze of different pore sizes, they position the nucleus ahead of the microtubule organizing center (MTOC) and use it to gauge the pores to identify the path of least resistance. Our aim was to identify whether dendritic cells adapt their migration strategy when encountering asymmetrical transitions into much denser environments with limited choice of large pores. In such invasive transitions it is unclear if the cells can cross tight pores without the use of adhesions and extracellular proteolysis and whether they maintain the nucleus in the cell front. Using various cell migration assays such as fibrous 3D collagen gels, geometrically defined microchannels with constrictions and simplistic under agarose migration assay, we provide a comprehensive characterization of invasive migration of dendritic cells. We show that during invasion the cells stall and stretch, reflecting the difficulty to translocate the bulky cell body into the dense environment. In collagen gels, we show that dendritic cells can invade without proteolysis and adhesions. Instead, they utilize contractility, which can lead to largescale collagen compressions. During invasion, the nucleus stalls at tight constrictions, leading to a transient organelle reorientation. To resolve the stalling, upregulated rear contractility is required. This contractile force is simultaneously necessary for reverting the nucleus back to the cell front after invasion and maintaining this positioning during permissive migration. A functional role of the reorientation was uncovered in the first collaboration project. A prominent central actin pool was identified around the MTOC, especially pronounced in dense and compressive environments. The actin pool was shown to generate pushing forces to dilate the space for cell translocation. These forces are only necessary in non-permissive environments, where the nucleus reorients to the cell rear, allowing the actin pool to generate space. In permissive environments where space generation is dispensable, the MTOC is located behind the nucleus and the actin cloud has reduced intensity, allowing more actin to be incorporated into the lamellipodium, speeding up migration. In the second collaboration project, we investigated the effects of distinct chemical environments on dendritic cell migration. The strikingly persistent migration of these cells was explained by their ability to modulate and even self-generate chemokine gradients. This allows the cells to migrate faster and more persistent in uniform chemokine fields compared to imposed chemokine gradients. The chemokine receptor CCR7 was identified as a crucial player in this process, both sensing the signal and internalizing the chemokine to create a sink.