Blimp-1 is a negative regulator of IL-2 signaling in T cells

Abstract

Abstract Interleukin-2 (IL-2) is a T cell growth factor with immunomodulatory effects and pleiotropic actions on T cells. IL-2 signaling occurs via the intermediate IL-2Rb and IL-2Rg and high-affinity IL-2Ra receptors, fine-tuning tolerance and effector functions. To investigate key regulators of the IL-2 signaling pathway, we performed genome-wide CRISPR-Cas9 screening in IL-2-dependent ED40515(+) cells, which were derived from a patient with HTLV-I associated Adult T Cell Leukemia. We found a significant dropout of sgRNAs for genes known to be important in IL-2 signaling, whereas sgRNAs targeting Prdm1 were highly enriched, with its being the top enriched hit in the screen. Prdm1 encodes Blimp-1, which is known to inhibit IL-2 production in T cells; however, its precise role in IL-2 signaling pathway remains elusive. Overexpression of Prdm1 resulted in lower expression of IL-2R subunits (CD25, CD122, CD132) and decreased IL-2-induced phosphorylation of STAT5, AKT, ERK in mouse CD4 +T cells. Correspondingly, conditional knockout (CKO) of Prdm1 in mouse CD4 +T cells and Tregs led to enhanced expression of IL-2R subunits, pSTAT5, pAKT and pERK. In an influenza infection mouse model, CD122 expression and pSTAT5 levels were higher in T follicular helper (T FH) cells from Prdm1 CKO mice as compared to WT T FHcells. Further, adoptive transfer of Prdm1 CKO Tregs into Rag1 −/−mice resulted in augmented IL-2 signaling and ameliorated inflammation in colitis. Concordantly, CRISPR/Cas9-mediated deletion of Prdm1 in human CD4 +T cells and Tregs resulted in increased expression of IL-2R subunits and IL-2-induced phosphorylation of STAT5, AKT and ERK. These results suggest that Blimp-1 is a negative regulator of IL-2 signaling in mouse and human T cells. Supported by intramural funding from NIH