The role of scatter factor receptor Met in mobilizing antigen presenting dendritic cells in vivo

• Die Bedeutung des Scatter-Factor-Rezeptors Met bei der Mobilisierung von antigen-präsentierenden dendritischen Zellen in vivo

Baek, Jea-Hyun; Zenke, Martin (Thesis advisor)

Aachen : Publikationsserver der RWTH Aachen University (2011)
Dissertation / PhD Thesis

Aachen, Techn. Hochsch., Diss., 2011

Abstract

Dendritic cells (DCs) are the major sentinels of immune surveillance system and a key link between innate and adaptive immunity by triggering T-cell specific immune responses. Thereby, the migratory properties of DCs are crucial for their immune function. Met is a receptor tyrosine kinase and the receptor for scatter factor (SF), also known as hepatocyte growth factor (HGF). Met signalling exhibits mitogenic, morphogenic and motogenic activity of various cells e.g. during embryonic development and wound healing. The functional expression of SF receptor/Met in skin DCs has been already shown. In this thesis, a detailed analysis of Met function in two major DC subpopulations in skin, dermal DCs (dDCs) and Langerhans cells (LCs), under steady-state and inflammatory conditions is presented by employing a conditional Met KO mouse model (Mx-Cre/Met fl/fl). In vivo, a distinct pattern of Met surface expression was found in different DC subpopulations, including dDCs and LCs in peripheral and lymphoid organs in steady-state. Activation of dDCs/LCs upon inflammation efficiently induced expression of Met both in vitro and in vivo. Dermal DC showed higher Met expression than LC and faster migration kinetics towards draining lymph nodes (LNs). Finally, genetic and pharmacological deficiency of Met severely impaired motility of dDCs/LCs resulting in failed mobilization of dDCs/LCs from skin and thus in disability of dDCs/LCs to mount an immune response in contact hypersensitivity reactions. Here, the regulation of matrix metalloproteinase activity by Met signalling was identified as one potential mechanism. Taken together, the data of this work demonstrate an essential function of Met for DC mobilization contributing to skin immunity and suggest new ways of treating autoimmune skin diseases.

Institutions

• [811001-1]