Chronic XBP1s signaling promotes B cell dysfunction and anergy

B cells are central mediators of humoral immunity, and their development is tightly regulated to prevent autoreactivity. The unfolded protein response (UPR) plays a crucial role in supporting the high biosynthetic demands of B cells. The transcription factor XBP1s, a key effector of the UPR’s IRE1α branch, has been implicated in plasma cell differentiation, but its role in early B cell development and tolerance remains unclear. Here we demonstrate that sustained activation of XBP1s shapes anergic B cell development and peripheral tolerance. We generated a B cell-specific XBP1s knock-in mouse model that induces chronic XBP1s expression. We find that chronic XBP1s overexpression drives the accumulation of anergic transitional 3 B cells, which exhibits attenuated activation responses to both BCR and TLR stimulation. Mechanistically, XBP1s overexpression upregulates the anergy-associated factor Egr2 and suppresses Irf4 expression. Our study provides insights into how dysregulated XBP1s expression may contribute to immune tolerance and dysfunction.