H3K4me3 mediates the NF-κB p50 homodimer binding to the pdcd1 promoter to activate PD-1 transcription in T cells

Priscilla S. Redd, Chunwan Lu, John D. Klement, Mohammed L. Ibrahim, Gang Zhou, Takumi Kumai, Esteban Celis, Kebin Liu

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere1483302
JournalOncoImmunology
Volume7
Issue number9
DOIs
StatePublished - Sep 2 2018

Fingerprint

T-Lymphocytes
CD8 Antigens
Immunologic Monitoring
CD4 Antigens
T-Cell Antigen Receptor
Autoimmunity
Immunotherapy
Transcriptional Activation
Neoplasms
Bone Marrow
Cell Line

Keywords

  • H3K4me3
  • NF-κB
  • PD-1
  • T cells
  • p50

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

H3K4me3 mediates the NF-κB p50 homodimer binding to the pdcd1 promoter to activate PD-1 transcription in T cells. / Redd, Priscilla S.; Lu, Chunwan; Klement, John D.; Ibrahim, Mohammed L.; Zhou, Gang; Kumai, Takumi; Celis, Esteban; Liu, Kebin.

In: OncoImmunology, Vol. 7, No. 9, e1483302, 02.09.2018.

Research output: Contribution to journalArticle

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AU - Lu, Chunwan

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AU - Ibrahim, Mohammed L.

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