Via siRNA-mediated knocking down, we observed that reducing Set1 in SLE CD4+ T cells down-regulated CREMα expression and Set1 binding at the CREMα promoter; accordingly, it decreased H3K4me3 enrichment within the same region, and increased IL-2 concentration, while inhibited IL-17A production. Here, SETD1A is linked to systemic lupus erythematosus.