The helix-loop-helix transcription factor Id3 regulates Marginal Zone B cell development and homeostasis 4849

Abstract Description Localized to the splenic marginal zone, Marginal Zone B cells (MZBs) have well-established functions such as orchestrating innate antibody responses to infections. However, mounting evidence supports an expanded role for MZBs beyond infection, especially in the context of autoimmunity. Given their importance in antigen shuttling and immune co-regulation, MZBs are attractive targets for cell-based immunotherapies. As such, a more complete understanding of the molecular mechanisms dictating MZB maintenance and function is needed. One regulator of B cells is the helix-loop-helix protein Id3, although the mechanism through which it modulates MZB cells is unclear. Using flow cytometry, we analyzed B cell-specific Id3-deficient mice and controls and confirmed that Id3 deficiency results in decreased MZBs, despite increased transitional 1 (T1) and follicular-II (FO-II) B cells, two known MZB progenitor populations. To investigate how loss of Id3 leads to these changes, we performed bulk-RNAseq on FACS-purified T1, FO-II, and MZBs as well as scRNAseq with paired BCRseq. We found that loss of Id3 has contrasting effects on T1/FO-II and MZB transcriptomes and GSEA revealed that Id3-deficient MZBs have decreased Notch pathway gene set enrichment, suggesting that Id3 may regulate Notch signaling in MZBs. These findings suggest that Id3 regulates both MZB differentiation and effector functions and motivate further studies of how these effects may impact autoimmunity. Funding Sources Supported by NIH 5T32AI007496-28, 2T32GM007267-42, 1F30HL176083-01 and the LeDucq Foundation B cells in CVD Transatlantic Network of Excellence. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)