Physiological levels of insulin induce receptor editing in anti-insulin B cells to maintain tolerance (128.18)

Abstract

Abstract Receptor editing (RE) is now recognized to play a major role in removing newly formed, autoreactive B cells from the repertoire. Although tolerance induction by monovalent BCR interactions may include clonal ignorance or anergy, it is not known if they can induce RE. Anti-insulin B cells harboring fixed Ig transgenes show evidence of attempted RE, including increased intracellular light chains and insulin-induced elevation of RAG-2 transcripts in vivo and in vitro. To formally test whether insulin could induce RE, we generated mice in which a targeted Ig Vκ encodes an anti-insulin BCR when paired with a fixed Ig VH125 transgene. This model allows the study of tolerance induced by Vκ RE when the BCR interacts with the non-cross-linking hormone, insulin. Anti-insulin B cells show strong evidence for RE in vivo; these findings suggest that BCR engagement with physiological levels of insulin trigger RE. This outcome was confirmed using bone marrow culture to demonstrate low levels of insulin effectively drive RE in vitro. These data extend the role of RE in tolerance to include regulation of BCRs directed at autoantigens such as protein hormones present at low concentrations. Accordingly, physiologically-regulated antigens may escape tolerance during reduced physiological demand or when emerging autoimmune disease reduces self antigen availability. Support provided by 5T32 HL069765, 5T32 GM08554, AI051448, and JDRF.