The capicua-ataxin-1-like complex regulates Notch-driven marginal zone B cell development and sepsis progression

Abstract

Follicular B (FOB) and marginal zone B (MZB) cells are pivotal in humoral immune responses against pathogenic infections. MZB cells can exacerbate endotoxic shock via interleukin-6 secretion. Here we show that the transcriptional repressor capicua (CIC) and its binding partner, ataxin-1-like (ATXN1L), play important roles in FOB and MZB cell development. CIC deficiency reduces the size of both FOB and MZB cell populations, whereas ATXN1L deficiency specifically affects MZB cells. B cell receptor signaling is impaired only in Cic -deficient FOB cells, whereas Notch signaling is disrupted in both Cic -deficient and Atxn1l -deficient MZB cells. Mechanistically, ETV4 de-repression leads to inhibition of Notch1 and Notch2 transcription, thereby inhibiting MZB cell development in B cell-specific Cic -deficient ( Cic f/f ;Cd19-Cre ) and Atxn1l -deficient ( Atxn1l f/f ;Cd19-Cre ) mice. In Cic f/f ;Cd19 - Cre and Atxn1l f/f ; Cd19-Cre mice, humoral immune responses and lipopolysaccharide-induced sepsis progression are attenuated but are restored upon Etv4 -deletion. These findings highlight the importance of the CIC-ATXN1L complex in MZB cell development and may provide proof of principle for therapeutic targeting in sepsis.