H3K4me3 mediates the NF-κB p50 homodimer binding to thepdcd1promoter to activate PD-1 transcription in T cells

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 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 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 promoter in CD4 and CD8 T cells. Deficiency in p50 results in reduced PD-1 expression in both CD4 and CD8 T cells . Using an 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 . The expression levels of H3K4me3-specific histone methyltransferase increased significantly, resulting in a significant increase in H3K4me3 deposition at the promoter in activated CD4 and CD8 T cells. Inhibition of H3K4me3 significantly decreased p50 binding to the promoter and PD-1 expression in a T cell line. Our findings determine that the p50-H3K4me3 axis regulates transcription activation in activated T cells.

Type I interferon suppresses tumor growth through activating the STAT3-granzyme B pathway in tumor-infiltrating cytotoxic T lymphocytes

“…Mixed BM chimera mice was created as previously described [26] using BM cells from SJL and IFNAR1-KO mice (at 1:1 ratio of SJL: IFNAR1-KO) (Additional file 1 Figure S2). Mice were immunized with the 2W1S peptide (EAWGALANWAVDSA) to activate CD4 + T cells [27] and with the OVA peptide (SIINFEKL) to activate CD8 + T cells [28] as previously described and analyzed for antigen-specific T cells as previously described [26].…”

Association between PD-1 and PD-L1 Polymorphisms and the Risk of Cancer: A Meta-Analysis of Case-Control Studies

“…Tumor cells express the programmed death-1-ligand 1 (PD-L1) as an adaptive, resistant mechanism to suppress the inhibitory receptor, namely programmed cell death-1 (PD-1) in order to evade host immunosurveillance [4]. PD-1, also known as PD1 and CD279, is a cell surface immunosuppressive receptor belonging to immunoglobulin superfamily and is encoded by the PDCD1 gene [5,6,7].…”

Interleukin‐37 improves T‐cell‐mediated immunity and chimeric antigen receptor T‐cell therapy in aged backgrounds

“…Given that treating aged mice with rIL‐37 significantly reduced chronic inflammation and was particularly effective at lowering circulating TNF‐α levels (Figure A,D), we next determined if rIL‐37 directly counteracted TNF‐α signaling and its ability to induce PD‐1 surface expression on aged T‐cells. In immune cells, TNF‐α is a potent inducer of NF‐κB activation (Liu et al, 2017) and NF‐κB binding sites are located in the PD‐1 promoter (Redd et al, 2018). In these studies, we found that treating aged CD4 + and CD8 + T‐cells with recombinant TNFα (rTNF‐α) significantly augmented NF‐κB activation in T‐cells (Figure 4a and Figure A) which correlated with increased PD‐1 surface expression on effector T‐cells (Figure 4b).…”