The Regulation of Human T-bethighCD21low B Cell Differentiation; Exploring Extrinsic and Intrinsic Factors

• Applicant: Dr. Baerbel Keller
• Subject Area: Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545533246

Human T-bethighCD21low B cells constitute an atypical B cell subset expanding in the peripheral blood of patients with autoimmune diseases like in Systemic lupus erythematosus (SLE), in Common Variable Immunodeficiency (CVID) and in chronic infection as in HIV. A capacity as proficient memory B cells, a bias to differentiate into antibody secreting cells or a state of terminal differentiation were discussed. Yet, their enriched antigen reactivity conveying a pathogenic potential especially in the context of autoimmune diseases, highlights the importance to pursue targeted treatment options. Crucially driven by IFNg/BCR stimulation, we previously showed a non-redundant role of T-cell help for the generation of T-bethighCD21low B cells. The transcription factor (TF) T-bet is crucial for the development and prominently contributes to the transcriptional regulation of this B cell subset. Yet, T-bet alone is not sufficient to induce the phenotype, but acts in a TF network jointly regulating gene expression. Our data imply that BATF and OCT2, highly expressed in CVID-derived T bethighCD21low B cells and commonly involved during initial steps of plasma cell differentiation, are involved in this network. In the current study, we aim to address the role of these TF, their induction, the temporal context and the mechanism of the alternative network that we expect to shape in the presence of T-bet. We anticipate the T-bet-centered network to govern the differentiation of T-bethighCD21low B cells compared to a plasma cell fate. Deepening the knowledge about these TF and the alternative network will improve the understanding of this population and allow to specifically interfere with its differentiation in a pathologic context. Moreover, we will address the role of altered STAT1 expression in B cells: we have observed increased levels of STAT1 in CD21pos B cells from CVID patients with a T-bethighCD21low B cell expansion. Potentially induced by the prevailing IFN milieu, the increased expression may imbalance JAK/STAT signalling downstream of different STAT1-dependent cytokines and alter target gene transcription. This shift may favour the differentiation of potentially harmful T-bethighCD21low B cells at the expense of classical memory or plasma cells. Thus, we will analyse increased STAT1 expression in other disease conditions associated with an expansion of T-bethighCD21low B cells. STAT1 will be overexpressed in primary human B cells and cytokine signalling as well as in vitro differentiation will be addressed. Our results will illuminate STAT1 as one of the suspected key factors in the development of these potentially pathogenic B cells and give hints for the use of JAKinibs in these patient cohorts. The results of this proposal will provide new insights into the fundamental role of TF networks in a T-bet-driven alternative B cell population, strongly associated with a chronically inflamed immune system, opening novel strategies for targeted treatment.

• DFG Programme: Research Grants