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Programmed death ligand 1 (PD-L1)-mediated induction of immune tolerance has been vigorously investigated in autoimmunity and anti-tumor immunity. However, details of the mechanism by which PD-L1 is induced in CD4 +  T cells are unknown. Here, we revealed the potential function of Klf1 and Egr2-mediated induction of PD-L1 in CD4 +  T cells. We focused on the molecules specifically expressed in CD4 + CD25 − LAG3 +  regulatory T cells (LAG3 +  Tregs) highly express of PD-L1 and transcription factor Egr2. Although ectopic expression of Egr2 induced PD-L1, a deficiency of Egr2 did not affect its expression, indicating the involvement of another PD-L1 induction mechanism. Comprehensive gene expression analysis of LAG3 +  Tregs and  in silico  binding predictions revealed that Krüppel-like factor 1 (Klf1) is a candidate inducer of the PD-L1 gene ( Cd274 ). Klf1 is a transcription factor that promotes β-globin synthesis in erythroid progenitors, and its role in immunological homeostasis is unknown. Ectopic expression of Klf1 induced PD-L1 in CD4 +  T cells through activation of the PI3K-mTOR signaling pathway, independent of STATs signaling and Egr2 expression. Our findings indicate that Klf1 and Egr2 are modulators of PD-L1-mediated immune suppression in CD4 +  T cells and might provide new insights into therapeutic targets for autoimmune diseases and malignancies.

Egr2-independent, Klf1-mediated induction of PD-L1 in CD4+ T cells