Here, our findings demonstrated that high AIM2 expression upregulates the TFH cell response and that the IL‐21‐AIM2‐TET2‐c‐MAF pathway contributes to autoimmune progression during lupus development, which may facilitate new clinical therapeutics targeting AIM2 in T cells for the treatment of SLE. Here, AIM2 is linked to systemic lupus erythematosus.