IL-21-STAT3 axis negatively regulates LAIR1 expression in B cells

Abstract LAIR1 is an inhibitory receptor broadly expressed on human immune cells, including B cells. LAIR1 has been shown to modulate BCR signaling, however, it is still unclear whether its suppressive activity can be a negative regulator for autoreactivity. In this study, we demonstrate the LAIR1 expression profile on human B cells and prove its regulatory function and relationships to B cell autoreactivity. We show that both the frequency and level of LAIR1 expression decreases during B cell differentiation. LAIR1 expressing (LAIR1+) switched memory (SWM) B cells have a transcriptional profile less differentiated toward a plasma cell (PC) phenotype, harbor more autoreactive B cells and exhibit less PC differentiation in vitro than the LAIR1 negative (LAIR1-) counterpart. These data suggests that LAIR1 functions as a B cell tolerance checkpoint. We confirm previous data showing that patients with systemic lupus erythematosus (SLE) express less LAIR1 on B cells, implying a breakdown of the checkpoint, consistent with the enhanced PC differentiation seen in SLE. We further demonstrate that LAIR1 expression is down-regulated through the IL-21/STAT3 pathway which is known to be upregulated in SLE. These data suggest therapeutic targets that might decrease the aberrant PC differentiation observed in SLE. Competing Interest Statement IKS is an employee of Eli Lilly Japan, but the present study was conducted independently of the company.