In BTN3A1 gene knock‐in (BTN3A1KI) mice, inflammation and lupus‐like manifestations occurred, including increased proportions of Th1, Th2, and Th17 cells, decreased Treg cells, elevated levels of inflammatory cytokines and anti‐dsDNA antibodies, renal injury, and suppressed IL‐38 serum levels. Here, BTN3A1 is linked to systemic lupus erythematosus.