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.