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 language | English (US) |
|---|---|
| Article number | e1483302 |
| Journal | OncoImmunology |
| Volume | 7 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2 2018 |
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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 journal › Article
}
TY - JOUR
T1 - H3K4me3 mediates the NF-κB p50 homodimer binding to the pdcd1 promoter to activate PD-1 transcription in T cells
AU - Redd, Priscilla S.
AU - Lu, Chunwan
AU - Klement, John D.
AU - Ibrahim, Mohammed L.
AU - Zhou, Gang
AU - Kumai, Takumi
AU - Celis, Esteban
AU - Liu, Kebin
PY - 2018/9/2
Y1 - 2018/9/2
N2 - 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.
AB - 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.
KW - H3K4me3
KW - NF-κB
KW - PD-1
KW - T cells
KW - p50
UR - http://www.scopus.com/inward/record.url?scp=85050590530&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050590530&partnerID=8YFLogxK
U2 - 10.1080/2162402X.2018.1483302
DO - 10.1080/2162402X.2018.1483302
M3 - Article
VL - 7
JO - OncoImmunology
JF - OncoImmunology
SN - 2162-4011
IS - 9
M1 - e1483302
ER -