Interleukin-2 (IL-2) regulates immune homeostasis by fine-tuning the balance between effector and regulatory T (Treg) cells. To identify regulators of IL-2 signaling, we performed genome-wide CRISPR-knockout screening in IL-2-dependent cells derived from a patient with adult T cell leukemia (ATL) and found enrichment of single guide RNAs targeting PRDM1, which encodes B lymphocyte-induced maturation protein 1 (BLIMP1). BLIMP1 inhibits IL-2 production by T cells; however, its role in IL-2 signaling remains unknown. Here, we show that overexpressing Prdm1 down-regulated IL-2 signaling, whereas Prdm1-deficiency enhanced IL-2 signaling in mouse CD4+ T cells and Treg cells with augmented IL-2 signaling in T cells from influenza-infected mice and during adoptive T cell transfer-induced colitis. Deleting PRDM1 in human CD4+ T cells and Treg cells also increased IL-2 signaling. Furthermore, CD4+ T cells from patients with ATL expressed less BLIMP1 and had enhanced IL-2 signaling, whereas overexpressing PRDM1 in ATL cells suppressed IL-2 signaling. Thus, BLIMP1 inhibits IL-2 signaling during normal and pathophysiological responses, suggesting that manipulating BLIMP1 could have therapeutic potential.