H3K4me3 mediates the NF-κB p50 homodimer binding to the pdcd1 promoter to activate PD-1 transcription in T cells. (2nd September 2018)

• Record Type: Journal Article
• Authors: Redd, Priscilla S.; Lu, Chunwan; Klement, John D.; Ibrahim, Mohammed L.; Zhou, Gang; Kumai, Takumi; Celis, Esteban; Liu, Kebin
• Is Part Of: Oncoimmunology. Volume 7:Number 9(2018)
• Publication Date: 2018-09-02
• Subjects: PD-1 -- T cells -- NF-κB -- H3K4me3 -- p50; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2018.1483302
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: PD-1 is a co-repressive receptor that curbs T cell activation and thereby serves as a protection mechanism against autoimmunity under physiological conditions. Under pathological conditions, tumor cells express PD-L1 as an adaptive resistant mechanism to suppress PD-1 + T cells to evade host immunosurveillance. PD-1 therefore is a key target in cancer immunotherapy. Despite the extensive studies of PD-1 expression regulation, the pdcd1 transcription machinery and regulatory mechanisms are still not fully understood. We report here that the NF-κB p50 homodimer is a transcription regulator of PD-1 in activated T cells. A putative κB sequence exists at the pdcd1 promoter. All five NF-κB Rel subunits are activated in activated T cells. However, only the p50 homodimer directly binds to the κB sequence at the pccd1 promoter in CD4 + and CD8 + T cells. Deficiency in p50 results in reduced PD-1 expression in both CD4 + and CD8 + T cells in vitro . Using an in vivo mixed bone marrow chimera mouse model, we show that p50 regulates PD-1 expression in a cell-intrinsic way and p50 deficiency leads to decreased PD-1 expression in both antigen-specific CD4 + and CD8 + T cells in vivo . The expression levels of H3K4me3-specific histone methyltransferase increased significantly, resulting in a significant increase in H3K4me3 deposition at the pdcd1 promoter in activated CD4 + and CD8 + T cells. Inhibition of H3K4me3 significantly decreased p50 binding to the pdcd1 promoter and PD-1 expression in a T cell line. Our findings determine that the p50-H3K4me3 axis regulates pdcd1 transcription activation in activated T cells.