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How these cells are poised not to respond and the mechanisms that restrain B cell responses to low-affinity endogenous antigens are not fully understood. Here, we demonstrate a critical role for the glycan-binding protein galectin-9 in setting the threshold of B cell activation and that loss of this regulatory network is sufficient to drive spontaneous autoimmunity. We further demonstrate a critical role for galectin-9 in restraining not only conventional B-2 B cells, but also innate-like B-1a cells. We show that galectin-9-deficient mice have an expanded population of B-1a cells and increased titers of B-1a-derived autoantibodies. Mechanistically, we demonstrate that galectin-9 regulates BCR and distinct TLR responses in B-1a cells, but not B-1b cells, by regulating the interaction between BCR and TLRs with the regulatory molecules CD5 and CD180, respectively. In the absence of galectin-9, B-1a cells are more readily activated and secrete increased titers of autoantibodies that facilitate autoantigen delivery to the spleen, driving autoimmune responses.<\/jats:p>","DOI":"10.7554\/elife.64557","type":"journal-article","created":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T07:00:41Z","timestamp":1628492441000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.64557","source":"Crossref","is-referenced-by-count":35,"title":["Galectin-9 regulates the threshold of B cell activation and autoimmunity"],"prefix":"10.7554","volume":"10","author":[{"given":"Logan K","family":"Smith","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of Toronto Scarborough, Toronto, Canada"},{"name":"Department of Immunology, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kareem","family":"Fawaz","sequence":"additional","affiliation":[{"name":"Department of Biological 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