Tu130 - Dissection of the Mechanisms That Drive Loss of B Cell Anergy During Development of Autoimmunity

Abstract Text:

Introduction: B cells play an essential role in T1D pathogenesis by priming autoreactive T cells; however, their specific function remains understudied. Upon leaving the bone marrow, mechanisms of peripheral tolerance render autoreactive B cells anergic. Anergy has been described in a subpopulation of naïve CD27-/IgM-/IgD+ B cells, coined Naïve IgD positive B cells (BND cells). We identified a novel subset of BND cells, termed BND2 cells, that exhibit elevated markers of activation, suggesting escape from anergy. We found BND2 cells are increased in the blood and pancreatic lymph node of T1D patients compared to controls. This project aims to identify mechanisms enabling BND2 cells to escape peripheral tolerance, compared to traditional BND cells, hereon referred to as BND1 cells.

Methods: We leveraged cell culture and murine models of T1D to identify soluble factors contributing to BND2 cell development. Using single-cell RNA-sequencing and machine learning algorithms, we compared the physicochemical properties of the BCR from BND2 cells to those of BND1 and other B cell subsets.

Results: We found that synergism of IFNγ and TLR7 agonism is essential for converting BND1 cells into BND2 cells. Additionally, our machine learning model reliably identifies autoreactive B cell subsets based on physicochemical properties, uncovering potential differences in how BND2 cells interact with autoantigens compared to other B cell subsets.

Conclusions: Our findings demonstrate that BND2 cells escape peripheral tolerance through mechanisms involving IFNγ and TLR7 signaling, coupled with unique physicochemical factors, which drives their activation and likely participation in autoimmunity.