Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells
© 2019 Maeda et al..
The inhibitory co-receptor programmed cell death 1 (PD-1, Pdcd1) plays critical roles in the regulation of autoimmunity, anticancer immunity, and immunity against infections. Immunotherapies targeting PD-1 have revolutionized cancer management and instigated various trials of improved cancer immunotherapies. Moreover, extensive trials are underway to potentiate PD-1 function to suppress harmful immune responses. Here we found that both natural and synthetic glucocorticoids (GCs) up-regulate PD-1 on T cells without altering the expression levels of other co-receptors and cell surface molecules. GC-induced up-regulation of PD-1 depended on transactivation of PD-1 transcription mediated through the glucocorticoid receptor. We further found that a GC response element 2525 bp upstream of the transcription start site of Pdcd1 is responsible for GC-mediated transactivation. We also observed that in vivo administration of GCs significantly up-regulates PD-1 expression on tumor-infiltrating T cells. By analyzing T cells differing in PD-1 expression, we directly demonstrated that the amount of PD-1 on the cell surface correlates with its inhibitory effect. Accordingly, GCs potentiated the capacity of PD-1 to inhibit T cell activation, suggesting that this PD-1-mediated inhibition contributes, at least in part, to the anti-inflammatory and immunosuppressive effects of GCs. In light of the critical roles of PD-1 in the regulation of autoimmunity, we expect that the potentiation of PD-1 activity may offer a promising therapeutic strategy for managing inflammatory and autoimmune diseases. Our current findings provide a rationale for strategies seeking to enhance the inhibitory effect of PD-1 by increasing its expression level.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:294 |
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| Enthalten in: |
The Journal of biological chemistry - 294(2019), 52 vom: 27. Dez., Seite 19896-19906 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Maeda, Natsumi [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.06.2020 Date Revised 05.02.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1074/jbc.RA119.010379 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM303264837 |
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| 245 | 1 | 0 | |a Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2019 Maeda et al. | ||
| 520 | |a The inhibitory co-receptor programmed cell death 1 (PD-1, Pdcd1) plays critical roles in the regulation of autoimmunity, anticancer immunity, and immunity against infections. Immunotherapies targeting PD-1 have revolutionized cancer management and instigated various trials of improved cancer immunotherapies. Moreover, extensive trials are underway to potentiate PD-1 function to suppress harmful immune responses. Here we found that both natural and synthetic glucocorticoids (GCs) up-regulate PD-1 on T cells without altering the expression levels of other co-receptors and cell surface molecules. GC-induced up-regulation of PD-1 depended on transactivation of PD-1 transcription mediated through the glucocorticoid receptor. We further found that a GC response element 2525 bp upstream of the transcription start site of Pdcd1 is responsible for GC-mediated transactivation. We also observed that in vivo administration of GCs significantly up-regulates PD-1 expression on tumor-infiltrating T cells. By analyzing T cells differing in PD-1 expression, we directly demonstrated that the amount of PD-1 on the cell surface correlates with its inhibitory effect. Accordingly, GCs potentiated the capacity of PD-1 to inhibit T cell activation, suggesting that this PD-1-mediated inhibition contributes, at least in part, to the anti-inflammatory and immunosuppressive effects of GCs. In light of the critical roles of PD-1 in the regulation of autoimmunity, we expect that the potentiation of PD-1 activity may offer a promising therapeutic strategy for managing inflammatory and autoimmune diseases. Our current findings provide a rationale for strategies seeking to enhance the inhibitory effect of PD-1 by increasing its expression level | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a PD-1 | |
| 650 | 4 | |a T cell | |
| 650 | 4 | |a T cell receptor (TCR) | |
| 650 | 4 | |a coreceptor | |
| 650 | 4 | |a cytokine induction | |
| 650 | 4 | |a gene expression | |
| 650 | 4 | |a glucocorticoid | |
| 650 | 4 | |a immune checkpoint | |
| 650 | 4 | |a immunology | |
| 650 | 4 | |a immunosuppression | |
| 650 | 7 | |a Anti-Inflammatory Agents |2 NLM | |
| 650 | 7 | |a Glucocorticoids |2 NLM | |
| 650 | 7 | |a Pdcd1 protein, mouse |2 NLM | |
| 650 | 7 | |a Programmed Cell Death 1 Receptor |2 NLM | |
| 650 | 7 | |a Receptors, Glucocorticoid |2 NLM | |
| 650 | 7 | |a Dexamethasone |2 NLM | |
| 650 | 7 | |a 7S5I7G3JQL |2 NLM | |
| 700 | 1 | |a Maruhashi, Takumi |e verfasserin |4 aut | |
| 700 | 1 | |a Sugiura, Daisuke |e verfasserin |4 aut | |
| 700 | 1 | |a Shimizu, Kenji |e verfasserin |4 aut | |
| 700 | 1 | |a Okazaki, Il-Mi |e verfasserin |4 aut | |
| 700 | 1 | |a Okazaki, Taku |e verfasserin |4 aut | |
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