Langerhans cells (LCs) are the dendritic cells (DCs) of the epidermis. They form the first contact site of the body to environmental antigens and pathogens. Despite their prominent role in the immune system, their full functional properties remain incompletely understood.
The development of LCs is strictly dependent on the cytokine TGF-beta1.
We previously performed a DNA microarray to compare TGF-beta1-treated and thereby LC-committed hematopoietic progenitors to cells of the monocytic lineage, in order to identify novel TGF-beta1-dependent genes that play a role in LC development and function.
The objective of this thesis was to analyze LC specific molecules identified in this screen. We focused on cell surface proteins towards identifying novel LC-specific markers and on transcription factors during LC lineage decision. We here identified the glycoprotein TROP2 as novel specific marker for human LCs. TROP2 is highly homologous to EpCAM, an established murine LC marker. We show that TROP2 is not expressed by other peripheral DCs aside from LCs and that all CD207+ DCs in the skin express TROP2. A key finding of this study was that human equivalents of murine CD207+ dermal resident DCs cannot be identified using the same strategy as in mice.
Furthermore, we identified previously unknown differences between LCs and human pulmonary DCs. Functional analyses revealed TROP2 as potential regulator of the cell cycle in LCs.
Additionally we show that the transcription factor KLF4 regulates LC differentiation in vivo in a mouse model. Whereas monocytic LC precursors are KLF4+, KLF4 is lost upon TGF-beta1-induced LC differentiation. Our data provide evidence for a functional role of KLF4, since stable ectopic expression of KLF4 diminishes LC differentiation. Moreover, KLF4 overexpression in this model enhances the development of splenic CD8alpha+ DCs. These data indicate a pronounced role for KLF4 during DC subset specification.