Regulation of B cell development and function by microRNA-191

• Applicant: Marcin Lyszkiewicz, Ph.D.
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 387697891

B cells are essential players of the immune system. They are among the most versatile immune cells. They are widely appreciated as a source of antibodies, their abilities to create antibodies against virtually any antigen is a fundament of adaptive immune response and vaccination. B cells are also recognized as crucial cells for optimal T cell responses by their ability to present antigen. Besides, they also secrete cytokines such as IL-10, IL-6, IL-17 and TGF-beta which regulate the activation and differentiation of T cells and also impact upon the development of autoimmune diseases. Finally, by expression of TNF-alpha and LT-beta they are also important in the formation of lymphoid tissue structure. Transcription factors and external signals that shape and modulate B cell fate are fairly well understood. However, regulation of B cell development by ncRNAs has not been systematically addressed. Among the ~1900 known microRNA (miRNAs), only few are described to influence steps in development and activation of B cells (e.g. miRNA 17~92, miR-34a, miR 150 and miR-155). Many more miRNA candidates are likely to exist. For instance, during my postdoctoral fellowshipwe identified miR-191 as an important regulator of the earliest B cell committed precursors. Using a gain-of-function approach in bone marrow chimeras, we showed that miR-191 targets E2A, FoxP1 and Egr-1, transcription factors which are essential for B cell differentiation. Taken together, these data suggest that miR-191 constrains B cell development by fine tuning a key B lineage transcriptional program.In this research proposal we aim to study how miR-191, member of novel call of genes which do not generate proteins but act postranscriptionally, regulate the lineage decision to become a B cell and its role in the generation of effective adaptive immune responses against the invading pathogens. In order to further explore the influence of miR-191 on development and function of B cells we generated miR-191 deficient mice. Deriving a picture of the regulatory network of B cells will help to understand basic mechanism of ncRNA action. Moreover, it will allow to deepen our understanding of fundamental process in which B cells acts. We hope that such knowledge will help to understand mechanism of leukeamia formation and can be potentially translated into therapeutic solution.

• DFG Programme: Research Grants