The role of Id2 (inhibitor of differentiation, DNA binding) in dendritic cell development in steady state and inflammation

Ober-Blöbaum, Juliane Luise (Author); Zenke, Martin (Thesis advisor)

Aachen / Publikationsserver der RWTH Aachen University (2009) [Dissertation / PhD Thesis]

Page(s): VIII, 113 S. : Ill., graph. Darst.

Abstract

Dendritic cells are professional antigen presenting cells that capture antigens and migrate to lymphoid tissues where they elicit specific immune responses. Several DC subtypes have previously been characterised, depending on their function and location. Each subtype appears to have a specialised role in both immunity and tolerance. However, less clear are the processes by which these different DC subsets develop from haematopoietic precursors, and the molecular mechanisms involved in the regulation of the different stages during DC development. The research described herein had the aim to continuatively characterize a previously described DC precursor, the Flt3+ progenitor, downstream of the haematopoietic stem cells, and to assess its developmental potential in vivo. Hereby, it was found that the Flt3+ progenitor does not only develop into dendritic cells, but can also generate all other cells of the haematopoietic compartment. Furthermore, this study examined the role of the HLH transcriptional regulator Id2 on the development of different DC subtypes, especially Langerhans cells. As monocytes had been assumed to be LC precursors, Gr-1hi monocytes as well as the Flt3+ progenitor were tested for their LC precursor potential. Using an Id2 knockout mouse model, it was found that Id2 is essential for the formation of Langerhans cells in steady state. Conversely, their development from Gr-1hi monocytes in response to inflammation is independent of Id2. Id2 is known to modulate the activity of E-proteins, such as E47, by antagonising their DNA binding. Therefore, the impact of Id2 and E47 on DC development was studied and this work provides new insights into the molecular mechanisms controlling the development of distinct DC subsets. It shows that the molecular mechanism by which Id2 controls the development of different DC subtypes is based on a modulation of E-proteins. Taken together, this research identified some of the key steps in the development of DCs downstream of the early haematopoietic precursors. It also dissected the contribution of different precursors for the Langerhans cell development in both the steady-state and during inflammation. Finally it provides evidence for the importance of Id2 and E proteins, such as E47 working in concert to regulate DC development and differentiation.