Kindlin-3 as a checkpoint in B cell immune responses and malignant transformation

• Applicant: Professorin Dr. Tanja Nicole Hartmann
• Subject Area: Hematology, Oncology ; Immunology ; Cell Biology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419090910

All aspects of B cell activation and differentiation, as well as their transformation into cancer cells, are controlled by the temporal and spatial relationship between the B cell and its microenvironment. Integrins control cellular functions by translating environmental signals into intracellular signals. In our previous work, we uncovered a novel role of the integrin adaptor kindlin-3. We described that the adaptor is a negative checkpoint of follicular B cell activation and further differentiation by affecting their CXCR5 responsiveness. This may affect antigen presentation by follicular dendritic cells (FDCs), formation of germinal centers during immune responses, and presumably affinity maturation of antibodies. We also found that kindlin-3 is required for onset of malignancy in a mouse model of chronic lymphocytic leukemia (CLL). In the follow-up project we aim to decipher the crosstalk of kindlin-3 with B-cell receptor (BCR) characteristics and signaling. We have developed several non-malignant as well as leukemic mouse models with a B-cell specific kindlin-3 knockout, some of which are tamoxifen-inducible. We have also deleted the gene encoding kindlin-3 using CRISPR/Cas9 in human B-cell lines, and will take advantage of our primary human CLL sample collection. Using a biomimetic microscopic approach, we will decipher the contribution of Kindlin-3 to the formation of the immune synapse between B cells and FDCs (Aim 1a). In addition, we will investigate the clustering of BCR molecules and their subsequent signal transduction by microscopic and cell biological approaches (Aims 1b, c). We will immunize the mouse models with T cell-dependent antigens and further characterize the contribution of kindlin-3 to these immune responses (Aim 2a). In addition, we will test whether T cell-independent immune responses and transport of antigens from blood to FDCs require kindlin-3 (Aims 2 b, c). The pathophysiology of CLL is strongly determined by the BCR and recently, we reported that the BCR-integrin axis is implicated in therapy resistance of this disease. Therefore, we will determine the specific impact of the leukemic BCR on immune synapse formation and the contribution of Kindlin-3 in this process (Aim 3). We will analyze the contribution of kindlin-3 to tumor infiltration of lymphoid organs and the impact of this molecule on disease progression, development of resistance to therapy, and transformation into highly aggressive lymphomas (Aim 4). With this project we hope to contribute to a better understanding of the pathophysiology of B-cell malignancies.

• DFG Programme: Research Grants