Research Group B Cell Development and Activation

Objectives

Studying the biology of Epstein-Barr Virus (EBV) is a very valuable tool to understand at least parts of the development and function of the human immune system, especially the B lymphocytes.

Work from different groups within the AGV and the former KMOLBI within the last three decades contributed considerably to the finding that EBV has evolved several of its viral proteins in a very sophisticated way to mimic activated cellular receptors, which are crucial in the molecular processes of B cell differentiation and activation – thereby leading to the successful establishment and maintenance of viral latency.

Interestingly, most of these proteins (LMP1, LMP2A, CD40, Notch) are also described to be associated with certain B cell lymphoma entities like Hodgkin´s Lymphoma (HL).

Our group is mainly interested in the establishment and analysis of conditional mouse models to study the role of these viral proteins as well as their cellular counterparts in B cell activation / differentiation and in lymphomagenesis.

Recently we established a mouse strain (rosa26 LMP1/CD40-stopflox), which is capable to express a constitutively activated CD40 receptor after Cre mediated deletion of a floxed stop cassette. The constitutive activity of the protein is achieved by fusion of the transmembrane part of LMP1 with the cytoplasmic part of CD40 leading to a CD40 ligand independent selfaggregation of the molecule and herewith activation.

B cell specific expression (by crossing with CD19-Cre mice) of this fusion protein results in a strong lymphoproliferation – observable for example by a splenomegaly – and in older mice to the development of B cell lymphomas with a high incidence.

We are now interested what signaling pathways downstream of the activated CD40 receptor are responsible for the lymphoproliferation and lymphomagenesis. For this purpose we are crossing LMP1/CD40//CD19-Cre mice with mice deficient for crucial components of single signalling pathways. One of the aspired results of these crossings would be a much more target-oriented tumor therapy of human B cell lymphomas with activated CD40 signaling.

A second mainline of our research is the study of deregulated Notch signalling in B lymphocytes. Notch receptors and their Epstein-Barr viral counterpart EBNA2 act as transcriptional activators, which interact with the cellular DNA binding protein RBP-Jk and induce the formation of a transcriptional activator complex leading to the transcription of target genes. Whereas EBNA2 is acting ligand independently the Notch receptors have to be induced by specific ligands (Delta and Jagged families) expressed on neighbouring cells. Ligand interaction leads to a sequence of proteolytical cleavages of the Notch receptor resulting in the nuclear translocation of the cytoplasmic part of Notch (NotchIC) and the subsequent transactivation of target genes.

Recently we established a mouse strain (rosa26 Notch2IC-stopflox), which is capable to express a constitutively activated Notch2 receptor after Cre mediated deletion of a floxed stop cassette. The constitutive activity of the protein is achieved by the expression of the cytoplasmic part of Notch2 (Notch2IC) which localizes ligand independently in the nucleus and transactivates RBP-Jk controlled target genes.

B cell specific expression (by crossing with CD19-Cre mice) of Notch2IC results in a strong conversion of the percentages of the two main mature B cell subsets in secondary lymphoid organs: Notch2IC expression drives all cells toward the MZ B-cell compartment at the expense of follicular B cells.

We are now interested (i) in the downstream effects of Notch2IC action, which are responsible for instructive role of Notch2IC in Marginal Zone B cell differentiation and (ii) in the role of Notch2 during B cell activation.

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