The role of T cells in chronic lymphotic leukaemia

Possible factors that may contribute to the development of B cell chronic lymphocytic leukaemia (CLL) are still poorly understood. Recent evidence from our own laboratory suggests the involvement of signalling by the B cell receptor and a role for T cells in the pathogenesis of this disease, as we observed a correlation between CLL disease progression and the occurrence of monoclonal T cell populations. In addition, we found a striking similarity in the usage of B cell receptor and T cell receptor genes among CLL patients, pointing to a direct CLL B/T cell interaction. The proposed project will allow us to shed light on the B/T cell synapse in CLL. This will involve identification and purification of T cells that directly interact with CLL B cells, assessment of their tumor supportive potency as well as a thorough characterization by comprehensive gene expression profiling. In addition, we will use our CLL mouse model to investigate the role of monoclonal and tumor specific T cells for disease development. This knowledge will certainly improve our understanding about lymphoma pathogenesis and will yield novel insights into T cell differentiation and T cell subset associated functions. Ultimately, our results will lead to the development of novel treatment approaches, as our concept introduces tumor specific T cells as a clinical target for CLL therapy.

In chronic lymphocytic leukemia (CLL) non-functional B cells grow in an uncontrolled manner. Genetic mutations in the affected CLL B cell and the interaction of different immune cells with the tumour B cells are crucial for the progression of the disease and the therapy. In this project we analysed the interaction of T cells and CLL B cells. We focused especially on the CD1d molecule that is express on the surface of CLL cells and binds lipids and lipophilic peptides (that can be tumour derived antigen). If a foreign and/or pathogenic molecule (e.g. tumour antigen) binds to the CD1d molecule, natural killer T cells (NKT cells) recognize the molecule on CD1d which subsequently leads to the activation of NKT cells. The activated NKT cell further activates other immune cells which finally leads to the elimination of the pathogenic B cell and prevents their expansion. Interestingly, we found that CLL B cells of many patients do no longer express CD1d molecules on their surface and thereby are invisible for NKT cells. This means that tumour cells cannot be recognized as malignant cells and will not be eliminated by the immune system. Additionally, we found that other T cell subgroups with distinct T cell receptors proliferate and express molecules (e.g. PD-1) which inhibit an immune attack against tumour cells. This new knowledge about T cells in CLL patients can help to reactivate the immune system and reprogram T cells to fight against the malignant B cells.