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Notch1 und Lymphotoxin Beta Receptor in Thymopoiesis
The thymus provides the appropriate microenvironments where bone marrow derived hematopoietic progenitors commit to the T lymphocyte lineage; supports their development; and finally shapes the repertoire of T cells. This thesis focuses on two defined points of T lymphocyte development. First, it deals with the commitment to the T cell lineage and later it turns to the induction of central tolerance in the thymus.
Notch1 receptor is essential for the early stages of T lymphocyte lineage development. Here we show that Notch signaling is already active in the bone marrow progenitors, and the intensity of signaling appears to increase in the earliest stages of T lymphopoiesis in the thymus. Despite that Notch signaling is active in the bone marrow, the absence of Notch 1 had no effect in the bone marrow progenitor populations. The obvious change concerns a very early block in T lymphocyte development in the thymus. It is shown here that T lymphocyte progenitors still reach the thymus and maintain T lymphocyte potential. Taken together, the results reveal that although Notch signaling starts in the bone marrow, the signaling through Notch1 receptor is only required upon entry of progenitors in the thymus. Most interestingly, Notch1 deficient progenitors maintain the capacity of seeding the thymus but fail to differentiate.
The second topic dealt with in this thesis concerns central tolerance induction in the thymus. This process relies on negative selection of self-specificities, and therefore the expression of self-antigens in the thymus is essential. Particularly, tissue specific antigens (TSAs) are expressed by medullary thymic epithelial cells (mTECs). The only known regulator of TSA expression by mTECs is Aire (autoimmune regulator), although some TSAs are not regulated by Aire. In this context, signaling through the lymphotoxin beta receptor (LTβR) was proposed to be upstream of Aire and both Aire-dependent and Aire-independent TSA expression. Here it is shown that LTβR deficient mice develop autoimmunity in a thymic stroma-dependent manner. Moreover, a whole-transcriptome analysis of LTβR deficient mTECs shows no evidence for the control of TSA by LTβR. Instead, a loss of transcripts involved in epithelial cell polarization and cell contact formation was detected. Consistently, histology of the LTβR deficient thymus revealed that mTECs present with an abnormal shape and cannot form the typical three-dimensional network characteristic of these cells. Evidence is presented that this defect impairs lympho-epithelial interaction and that this might be the reason for autoimmunity in these mice. Taken together, the results indicate that central tolerance induction requires not only the expression of self-antigens but also this must occur in an ideal display format that optimizes lympho-epithelial interaction.
Die vorliegende Doktorarbeit beschäftigt sich mit der Stammzelldifferenzierung zur T-Zelllinie und der damit verbundenen Problematik der Toleranzentstehung im Thymus.
|Institut:||Institut für Biologie 1 (Zoologie)|
|Fakultät:||Fakultät für Biologie|
|Erstgutachter:||Boehm, Thomas (Prof. Dr.)|
|Tag der mündlichen Prüfung:||07.11.2007|