The impact of Met signaling on DC motility, migration and immune response

  • Der Einfluss des Met-Signalwegs in dendritischen Zellen auf Motilität, Migration und Immunantwort

Hamouda, Ahmed Emad Ibrahim; Zenke, Martin (Thesis advisor); Panstruga, Ralph (Thesis advisor)

Aachen : RWTH Aachen University (2021, 2022)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021


Dendritic cells (DC) are the most efficient antigen presenting cells and a key bridge between the innate and adaptive immune systems. Immature DC reside in lymphoid and non-lymphoid organs, acting as sentinels of the immune system. In the skin, Langerhans cells (LC), the epidermal DC subset, and dermal DC (dDC) form an initial immune barrier to invading pathogens by carrying, processing and presenting pathogenic antigens to T cells in the draining lymph node (dLN), thereby mounting an adaptive immune response. Therefore, efficient LC and dDC migration to the dLN is crucial for their function. The receptor tyrosine kinase (RTK) Met is the only known receptor for hepatocyte growth factor (HGF), which promotes motogenic activities in certain physiological (e.g. organogenesis and wound healing) and pathological (e.g. metastasis) contexts. Met is expressed on antigen presenting cells (APC) including LC and dDC. It was shown that Met is a key regulator of skin DC migration to the dLN. However, the molecular mechanisms by which Met regulates DC migration are not yet fully understood. In this study, the impact of Met signaling on various DC migratory properties including adhesion, chemotaxis, podosome formation and gelatin degradation was investigated. By employing a conditional Met-deficient mouse model, Met signaling was found to have no impact on LC detachment from surrounding tissue and their mobilization. However, Met-deficient LC failed to degrade the basement membrane. Met signaling was shown to be essential for podosome formation in DC in the absence of HGF, through the downstream Gab1-Shp2-MAPK axis, thereby controlling their ability to degrade the basement membrane. To address the role of Gab1 in DC migration, a conditional Gab1-deficient mouse model was established. Gab1 deficiency in LC and dDC impaired their migration ex vivo and in vivo. Consequently, Gab1-deficient mice failed to mount a proper contact hypersensitivity (CHS) reaction. Finally, both Met and Gab1 were shown to be indispensable for HGF-induced DC motility in a 3D environment. Taken together, our results indicate that Met signaling regulates DC migration through the Gab1-Shp2-MAPK axis in HGF-dependent and HGF-independent manners.