PT - JOURNAL ARTICLE AU - Etienne Masle-Farquhar AU - Timothy Peters AU - Katherine JL Jackson AU - Mandeep Singh AU - Cindy S Ma AU - Daniel Suan AU - Gulbu Uzel AU - Ignatius Chua AU - Jennifer W Leiding AU - Kaarina Heiskanen AU - Kahn Preece AU - Leena Kainulainen AU - Michael O’Sullivan AU - Megan A Cooper AU - Mikko RJ Seppänen AU - Satu Mustjoki AU - Shannon Brothers AU - Tiphanie P Vogel AU - Robert Brink AU - Stuart G Tangye AU - Joanne H Reed AU - Christopher C Goodnow TI - Overactive STAT3 drives accumulation of disease-associated CD21<sup>low</sup> B cells AID - 10.1101/2021.12.20.473595 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.12.20.473595 4099 - http://biorxiv.org/content/early/2021/12/21/2021.12.20.473595.short 4100 - http://biorxiv.org/content/early/2021/12/21/2021.12.20.473595.full AB - Dysregulated STAT3 signalling is correlated with antibody-mediated autoimmunity and B- cell neoplasia, but its effect on B cells is underexplored. Here we address this in children with STAT3 gain-of-function (GOF) syndrome and in mice with STAT3T716M, the most common STAT3 GOF syndrome human mutation, or STAT3K658N, a dimerization interface mutation responsible for STAT3 GOF syndrome in two children. The main B cell consequence of overactive STAT3 was accumulation of CD19high CD21low atypical memory B cells in humans and of CD21low CD23low B cells in mice resembling age-associated B cells expressing T-bet, CD11c and plasma cell differentiation genes. Overactive STAT3 within B cells increased expression of many genes in the B cell receptor and T cell help pathways, increased the tolerogenic receptor CD22, but opposed B cell tolerance checkpoints and increased formation of T-bet+ B cells upon BCR and CD40 stimulation. These results reveal overactive STAT3 as a central driver of a key class of disease- associated B-lymphocytes in humans and mice.Competing Interest StatementThe authors have declared no competing interest.