Distinct STING-IRF3 activation determines IL-35 Breg differentiation in rodent malaria.

Augmented regulatory B cell (Breg) responses are commonly observed in malaria; however, the specific parasite components and Breg subtypes involved remain unclear. In this study, we investigated C57BL/6 mice infected with Plasmodium berghei ANKA, which induces cerebral malaria pathology, in comparison to P. yoelii YM, which does not. We found that distinct Breg types differentiated in response to these infections, driven by hemozoin-mediated Toll-like receptor 9 activation. Interleukin-35-positive (IL-35) Breg expansion occurred in P. yoelii YM-infected mice but not in those infected with P. berghei ANKA. We demonstrated that stimulator of interferon genes (STING)-mediated interferon regulatory factor 3 (IRF3) phosphorylation suppressed IL-35 Breg differentiation, potentially contributing to experimental cerebral malaria (ECM). In contrast, P. yoelii YM infection activated IRF3 in a STING-independent manner, promoting IL-35 Breg expansion. These findings highlight IL-35 Bregs as key modulators in malarial immunopathology.