Elucidation of the physiological impact of regulatory B cells and regulatory B cell-derived IgA on mucosal immunity by employing novel genetic animal models

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Increasing clinical evidence links recently described immunoregulatory B cells to human disease. However, many of the basic questions on the cellular nature and mechanism of function of these regulatory B cells are still largely unknown. In this follow-up application, we address so far unresolved questions of the immunomodulatory mechanisms of regulatory B cells and aim to elucidate the physiological impact of these cells and their descendants on chronic intestinal inflammation and inflammation-associated tumorigenesis by using novel genetic animal models. In our previous studies, we analyzed functional characteristics of regulatory B cells (Bregs) and identified an inherent capacity of Bregs to differentiate into IgA plasma cells. Furthermore, our studies indicate that Breg-derived IgA antibodies promote the development of a beneficial microbial composition during the progression of chronic colitis and colitis-associated colorectal cancer. Building up on these intriguing new aspects of regulatory B cell biology that we uncovered in the previous funding period, we here aim to further characterize the physiological function of Breg-derived IgA in controlling the intestinal microbiota by establishing an innovative IL-10-lineage-tracing reporter mouse model. This reporter model will enable us for the first time to unequivocally identify Breg-derived IgA-producing plasma cells in vivo in a whole animal system and to study their induction and homing characteristics under normal and diseased conditions. These studies will also include the cloning of recombinant Breg-derived IgA antibodies by employing single-cell BCR-repertoire profiling of Breg-derived IgA plasma cells and characterization of their antigen-specificity as well as their functional activities on the intestinal microbiota. Furthermore, the previous DFG-funding enabled us to generate a transgenic mouse that specifically overexpresses the ‘Breg-regulator’ Fcmr(Toso) on B cells. Based on our previous studies, these mice are expected to have reduced numbers or even absence of Bregs and, thus, provide a unique animal model to study the physiological relevance of Bregs in the development of inflammatory disease. As Fcmr(Toso)-overexpression is tightly associated with B cell malignancy, these mice may also serve as a novel cancer model. Therefore, in the second part of our studies, we will perform a detailed phenotypical characterization of these novel transgenic mice with specific focus on the development of chronic inflammatory immune disorders, as well as B cell-related tumorigenesis. Together, the results from our proposed studies will lead to principal conceptual advances in our understanding of regulatory B cell-mediated protective mechanisms in the control of chronic inflammation and may even open up novel therapeutic prospects of using Breg-derived IgA antibodies in inflammatory disease.