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Cited by 224T-cell and B-cell ImmunologyTelomeres, Telomerase, and SenescenceCancer Immunotherapy and Biomarkers

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Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition

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Liu, Xia, Mo, Wei, Ye, Jian, Li, Lingyun, Zhang, Yanping, Hsueh, Eddy C., Hoft, Daniel F., Peng, Guangyong·2018·Nature Communications
DOI 10.1038/s41467-017-02689-5PMC PMC5770447
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Abstract

Defining the suppressive mechanisms used by regulatory T (Treg) cells is critical for the development of effective strategies for treating tumors and chronic infections. The molecular processes that occur in responder T cells that are suppressed by Treg cells are unclear. Here we show that human Treg cells initiate DNA damage in effector T cells caused by metabolic competition during cross-talk, resulting in senescence and functional changes that are molecularly distinct from anergy and exhaustion. ERK1/2 and p38 signaling cooperate with STAT1 and STAT3 to control Treg-induced effector T-cell senescence. Human Treg-induced T-cell senescence can be prevented via inhibition of the DNA damage response and/or STAT signaling in T-cell adoptive transfer mouse models. These studies identify molecular mechanisms of human Treg cell suppression and indicate that targeting Treg-induced T-cell senescence is a checkpoint for immunotherapy against cancer and other diseases associated with Treg cells.

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Fig. 1 Human nTreg and γδ Treg cells induce DNA damage response in responder T cells. a, b Phosphorylated activation of ATM and other associated molecules H2AX, 53BP1, and CHK2 in both naive CD4+ T (in a) and naive CD8+ T (in b) cells treated with CD4+CD25hiFoxP3+ Treg (nTreg) cells. Anti-CD3 activated naive T cells were treated with nTreg or CD4+CD25− effector T cells (control) for 3 days. The p-ATM, p-H2AX, p-53BP1, and p-CHK2 expression in treated naive CD4+ and CD8+ T cells were analyzed by the flow cytometry. c, d Upregulated phosphorylated ATM and other associated molecules H2AX, 53BP1, and CHK2 were determined in pre-activated naive CD4+ (in c) and CD8+ (in d) T cells treated with γδ Treg cells for 3 days by the flow cytometry. Anti-CD3-activated naive T cells treated with CD4+CD25− and γδ2 effector T cells were served as controls
Fig. 1 Human nTreg and γδ Treg cells induce DNA damage response in responder T cells. a, b Phosphorylated activation of ATM and other associated molecules H2AX, 53BP1, and CHK2 in both naive CD4+ T (in a) and naive CD8+ T (in b) cells treated with CD4+CD25hiFoxP3+ Treg (nTreg) cells. Anti-CD3 activated naive T cells were treated with nTreg or CD4+CD25− effector T cells (control) for 3 days. The p-ATM, p-H2AX, p-53BP1, and p-CHK2 expression in treated naive CD4+ and CD8+ T cells were analyzed by the flow cytometry. c, d Upregulated phosphorylated ATM and other associated molecules H2AX, 53BP1, and CHK2 were determined in pre-activated naive CD4+ (in c) and CD8+ (in d) T cells treated with γδ Treg cells for 3 days by the flow cytometry. Anti-CD3-activated naive T cells treated with CD4+CD25− and γδ2 effector T cells were served as controlsCC BY · PubMed Central
Fig. 2 Blocking ATM-associated DNA damage response prevents human Treg-induced T-cell senescence. a, b Pretreatment of naive CD4+ (in a) and CD8+ (in b) T cells with ATM inhibitor KU55933 significantly decreased senescent T-cell populations in responder T cells induced by nTreg cells. Anti-CD3 activated T cells were pretreated with or without KU55933 (10 μM) for 1 day, and then co-cultured with human nTreg cells for 3 days. SA-β-Gal expression in naive CD4+ and CD8+ T cells was determined with SA-β-Gal staining. The SA-β-Gal positive T cells were identified with dark blue granules as indicated by the arrows. Scale bar: 20 μm. Data shown in the right panels are mean ± SD from three independent experiments, and paired t test was performed. **p < 0.01, compared with the control CD4+CD25− and KU55933 treatment groups. #p < 0.01, compared with the control CD4+CD25− T cell treatment group. c, d Pretreatment of responder T cells with ATM inhibitor KU55933 markedly restored CD27 and CD28 expression in Treg-treated naive CD4+ (in c) and CD8+ (in d) T cells. CD27 and CD28 expression in treated naive CD4+ T cells as described in a and b were analyzed by the flow cytometry. e, f DNA damage response molecules and cell cycle regulatory molecules are co-expressed in human Treg-induced senescent CD4+ T cells as described in Fig. 1. Immunofluoresence double staining with antibodies against p-ATM, p-H2AX, p-53BP1, or p-CHK2 with anti-P16, P53, or P21antibodies in the same slide from responder T cells treated with Treg or control CD4+CD25− effector T cells. Scale bar: 20 μm
Fig. 2 Blocking ATM-associated DNA damage response prevents human Treg-induced T-cell senescence. a, b Pretreatment of naive CD4+ (in a) and CD8+ (in b) T cells with ATM inhibitor KU55933 significantly decreased senescent T-cell populations in responder T cells induced by nTreg cells. Anti-CD3 activated T cells were pretreated with or without KU55933 (10 μM) for 1 day, and then co-cultured with human nTreg cells for 3 days. SA-β-Gal expression in naive CD4+ and CD8+ T cells was determined with SA-β-Gal staining. The SA-β-Gal positive T cells were identified with dark blue granules as indicated by the arrows. Scale bar: 20 μm. Data shown in the right panels are mean ± SD from three independent experiments, and paired t test was performed. **p < 0.01, compared with the control CD4+CD25− and KU55933 treatment groups. #p < 0.01, compared with the control CD4+CD25− T cell treatment group. c, d Pretreatment of responder T cells with ATM inhibitor KU55933 markedly restored CD27 and CD28 expression in Treg-treated naive CD4+ (in c) and CD8+ (in d) T cells. CD27 and CD28 expression in treated naive CD4+ T cells as described in a and b were analyzed by the flow cytometry. e, f DNA damage response molecules and cell cycle regulatory molecules are co-expressed in human Treg-induced senescent CD4+ T cells as described in Fig. 1. Immunofluoresence double staining with antibodies against p-ATM, p-H2AX, p-53BP1, or p-CHK2 with anti-P16, P53, or P21antibodies in the same slide from responder T cells treated with Treg or control CD4+CD25− effector T cells. Scale bar: 20 μmCC BY · PubMed Central
Fig. 3 Treg-mediated glucose competition causes responder T-cell senescence and DNA damage. a Higher expression levels of glucose transporters (Glut1 and Glut3) in Treg cells than that of effector T cells analyzed by real-time PCR. Expression levels of each gene were normalized to β-actin expression and adjusted to the levels in CD4+CD25− cells only (served as 1). Data shown are mean ± SD from four independent donors. b Human nTreg and tumor-derived γδ Treg cells have a high glucose uptake capacity determined by the flow cytometry after addition of 2-NBDG. Results shown are a representative of four independent experiments. c Co-culture of nTreg with naïve CD4+ T cells for 3 days significantly decreased glucose levels in the culture medium. **p < 0.01, compared with naive T cells in medium only group by unpaired t test. d Increased phosphorylation of AMPK was induced in naive CD4+ T cells treated with nTreg cells. The p-AMPK and total AMPK expression in treated T cells for 3 days was analyzed by the flow cytometry. e Low concentrations of glucose significantly promoted phosphorylation of AMPK in anti-CD3-activated naive CD4+ T cells for 3 days using the flow cytometry analysis. f, g Inhibition of glucose transport and glycolysis dramatically blocked Treg suppressive capacity on T-cell proliferation (in f) and responder T-cell senescence induction (in g). Treg cells were pretreated with inhibitors phloretin (2 μM) or 2-DG (1 mM) for 1 day, and then co-cultured with naive CD4+ T cells for 3 days. Data shown are mean ± SD from three independent experiments.*p < 0.05 and **p < 0.01, compared with the medium only group by paired t test. h Addition of high concentrations of glucose markedly rescued responder T-cell senescence induced by Treg cells determined with SA-β-Gal staining after 3-day co-culture. Data shown are mean ± SD from three independent experiments. **p < 0.01, compared with the Treg-treated group with normal concentration of glucose (11 mM) using paired t test. i High concentrations of glucose significantly prevented the DNA damage-associated molecule activation in responder T cells induced by nTreg cells for 3 days using the flow cytometry analyses
Fig. 3 Treg-mediated glucose competition causes responder T-cell senescence and DNA damage. a Higher expression levels of glucose transporters (Glut1 and Glut3) in Treg cells than that of effector T cells analyzed by real-time PCR. Expression levels of each gene were normalized to β-actin expression and adjusted to the levels in CD4+CD25− cells only (served as 1). Data shown are mean ± SD from four independent donors. b Human nTreg and tumor-derived γδ Treg cells have a high glucose uptake capacity determined by the flow cytometry after addition of 2-NBDG. Results shown are a representative of four independent experiments. c Co-culture of nTreg with naïve CD4+ T cells for 3 days significantly decreased glucose levels in the culture medium. **p < 0.01, compared with naive T cells in medium only group by unpaired t test. d Increased phosphorylation of AMPK was induced in naive CD4+ T cells treated with nTreg cells. The p-AMPK and total AMPK expression in treated T cells for 3 days was analyzed by the flow cytometry. e Low concentrations of glucose significantly promoted phosphorylation of AMPK in anti-CD3-activated naive CD4+ T cells for 3 days using the flow cytometry analysis. f, g Inhibition of glucose transport and glycolysis dramatically blocked Treg suppressive capacity on T-cell proliferation (in f) and responder T-cell senescence induction (in g). Treg cells were pretreated with inhibitors phloretin (2 μM) or 2-DG (1 mM) for 1 day, and then co-cultured with naive CD4+ T cells for 3 days. Data shown are mean ± SD from three independent experiments.*p < 0.05 and **p < 0.01, compared with the medium only group by paired t test. h Addition of high concentrations of glucose markedly rescued responder T-cell senescence induced by Treg cells determined with SA-β-Gal staining after 3-day co-culture. Data shown are mean ± SD from three independent experiments. **p < 0.01, compared with the Treg-treated group with normal concentration of glucose (11 mM) using paired t test. i High concentrations of glucose significantly prevented the DNA damage-associated molecule activation in responder T cells induced by nTreg cells for 3 days using the flow cytometry analysesCC BY · PubMed Central
Fig. 4 STAT1 and SATA3 control responder T-cell senescence mediated by human Treg cells. a Transcriptome analyses showed that c-Myc, SP1, STAT1, and STAT3 were the most significantly altered transcription factors in Treg-induced senescent CD8+ T cells. Gene alterations involved in transcription factors and related signaling pathways were identified and ranked in naive CD8+ T cells after treatment with or without nTreg cells at different time points. b Phosphorylated activation of STAT1 and STAT3 in senescent CD4+ T cells induced by nTreg cells. Results from western blot analyses of phosphorylated activation of STAT1, STAT3, SP1, and c-Myc are shown in the left panel. Phosphorylated STAT1 and STAT3 protein levels shown in the right histogram were quantitatively analyzed and compared against the GAPDH expression levels with a densitometer. Results shown in the histogram are mean ± SD from three independent experiments. **p < 0.01 compared with the CD4+CD25- control group using paired t test. c, d Inhibition of STAT1 or STAT3 signaling by specific pharmacological inhibitors significantly suppressed STAT1 and STAT3 phosphorylation and decreased SA-β-Gal expression in T cells treated by Treg cells. Anti-CD3-activated naïve CD4+ T cells were pretreated with or without JAK and/or STAT inhibitors tyrphostin AG490 (30 μM, JAK inhibitor), MTA (5 μM, STAT1 inhibitor) or S3I-201 (10 μM, STAT3 inhibitor) for 1 day. The STAT activity-blocked or -unblocked T cells were then cultured with human Treg cells at a ratio of 4:1 for different time points (0, 3, 5 days) and studied for STAT1 and STAT3 activation with western blot analysis (in c) and SA-β-Gal expression (in d). Data shown are mean ± SD from three independent experiments, and paired t test was performed. **p < 0.01, compared with the group not treated with inhibitors. e Phosphorylated STAT3 was co-expressed with phosphorylated ATM and P53 in senescent T cells induced by human Treg cells. Immunofluoresence double staining with antibodies against STAT3, and p-ATM or P53 in the same slide of responder T cells treated with Treg or control CD4+CD25− effector T cells. Scale bar: 20 μm
Fig. 4 STAT1 and SATA3 control responder T-cell senescence mediated by human Treg cells. a Transcriptome analyses showed that c-Myc, SP1, STAT1, and STAT3 were the most significantly altered transcription factors in Treg-induced senescent CD8+ T cells. Gene alterations involved in transcription factors and related signaling pathways were identified and ranked in naive CD8+ T cells after treatment with or without nTreg cells at different time points. b Phosphorylated activation of STAT1 and STAT3 in senescent CD4+ T cells induced by nTreg cells. Results from western blot analyses of phosphorylated activation of STAT1, STAT3, SP1, and c-Myc are shown in the left panel. Phosphorylated STAT1 and STAT3 protein levels shown in the right histogram were quantitatively analyzed and compared against the GAPDH expression levels with a densitometer. Results shown in the histogram are mean ± SD from three independent experiments. **p < 0.01 compared with the CD4+CD25- control group using paired t test. c, d Inhibition of STAT1 or STAT3 signaling by specific pharmacological inhibitors significantly suppressed STAT1 and STAT3 phosphorylation and decreased SA-β-Gal expression in T cells treated by Treg cells. Anti-CD3-activated naïve CD4+ T cells were pretreated with or without JAK and/or STAT inhibitors tyrphostin AG490 (30 μM, JAK inhibitor), MTA (5 μM, STAT1 inhibitor) or S3I-201 (10 μM, STAT3 inhibitor) for 1 day. The STAT activity-blocked or -unblocked T cells were then cultured with human Treg cells at a ratio of 4:1 for different time points (0, 3, 5 days) and studied for STAT1 and STAT3 activation with western blot analysis (in c) and SA-β-Gal expression (in d). Data shown are mean ± SD from three independent experiments, and paired t test was performed. **p < 0.01, compared with the group not treated with inhibitors. e Phosphorylated STAT3 was co-expressed with phosphorylated ATM and P53 in senescent T cells induced by human Treg cells. Immunofluoresence double staining with antibodies against STAT3, and p-ATM or P53 in the same slide of responder T cells treated with Treg or control CD4+CD25− effector T cells. Scale bar: 20 μmCC BY · PubMed Central
Fig. 5 MAPK cooperates with STAT to control T-cell senescence mediated by Treg cells. a Pretreatment of naive CD4+ T cells with an ATM inhibitor KU55933 significantly prevented P38 and ERK phosphorylation in responder T cells treated by nTreg cells using western blot analyses. Anti-CD3 activated CD4+ T cells were pretreated with or without KU55933 (10 μM) for 1 day, and then co-cultured with nTreg cells for different time points. Protein levels of phosphorylated P38 and ERK shown in the right histogram were quantitatively analyzed and compared against the GAPDH expression levels with a densitometer. Results shown in the histogram are mean ± SD from three independent experiments. **p < 0.01, compared with the medium only and KU55933 treatment groups by paired t test. b Phosphorylated P38 and ERK were co-expressed with cell cycle regulatory molecules P16 and P53 in human Treg-induced senescent CD4+ T cells. Immunofluoresence double staining with antibodies against p-ERK and p-P38 with anti-P16 or P53 antibodies in the same slide of responder T cells treated with Treg or control CD4+CD25- effector T cells. Scale bar: 20 μm. c Inhibition of ERK1/2 or p38 signaling pathways by specific pharmacological inhibitors markedly blocked the STAT1 and STAT3 phosphorylation in responder T cells treated by Treg cells. Anti-CD3 activated CD4+ T cells were pretreated with inhibitors U0126 or SB203580 (10 μM) for 1 day, and then co-cultured with nTreg cells for different time points. Phosphorylation of p38, ERK, STAT1 and STAT3 was determined by western blot analyses. d Pretreatment of naive CD4+ T cells with an ATM inhibitor KU55933 significantly prevented STAT1 and STAT3 phosphorylation in responder T cells treated by Treg cells. Cell treatment and procedure is identical as described in a. Phosphorylation of STAT1 and STAT3 was determined by western blot analyses. e Phosphorylated P38 and ERK were co-expressed with phosphorylated STAT3 in senescent CD4+ T cells induced by human Treg cells. Immunofluoresence double staining with antibodies against p-ERK and p-P38 with anti-p-STAT3 in the same slide of responder T cells treated with Treg or control CD4+CD25− effector T cells. Scale bar: 20 μm
Fig. 5 MAPK cooperates with STAT to control T-cell senescence mediated by Treg cells. a Pretreatment of naive CD4+ T cells with an ATM inhibitor KU55933 significantly prevented P38 and ERK phosphorylation in responder T cells treated by nTreg cells using western blot analyses. Anti-CD3 activated CD4+ T cells were pretreated with or without KU55933 (10 μM) for 1 day, and then co-cultured with nTreg cells for different time points. Protein levels of phosphorylated P38 and ERK shown in the right histogram were quantitatively analyzed and compared against the GAPDH expression levels with a densitometer. Results shown in the histogram are mean ± SD from three independent experiments. **p < 0.01, compared with the medium only and KU55933 treatment groups by paired t test. b Phosphorylated P38 and ERK were co-expressed with cell cycle regulatory molecules P16 and P53 in human Treg-induced senescent CD4+ T cells. Immunofluoresence double staining with antibodies against p-ERK and p-P38 with anti-P16 or P53 antibodies in the same slide of responder T cells treated with Treg or control CD4+CD25- effector T cells. Scale bar: 20 μm. c Inhibition of ERK1/2 or p38 signaling pathways by specific pharmacological inhibitors markedly blocked the STAT1 and STAT3 phosphorylation in responder T cells treated by Treg cells. Anti-CD3 activated CD4+ T cells were pretreated with inhibitors U0126 or SB203580 (10 μM) for 1 day, and then co-cultured with nTreg cells for different time points. Phosphorylation of p38, ERK, STAT1 and STAT3 was determined by western blot analyses. d Pretreatment of naive CD4+ T cells with an ATM inhibitor KU55933 significantly prevented STAT1 and STAT3 phosphorylation in responder T cells treated by Treg cells. Cell treatment and procedure is identical as described in a. Phosphorylation of STAT1 and STAT3 was determined by western blot analyses. e Phosphorylated P38 and ERK were co-expressed with phosphorylated STAT3 in senescent CD4+ T cells induced by human Treg cells. Immunofluoresence double staining with antibodies against p-ERK and p-P38 with anti-p-STAT3 in the same slide of responder T cells treated with Treg or control CD4+CD25− effector T cells. Scale bar: 20 μmCC BY · PubMed Central
Fig. 6 Senescent T cells induced by human Treg cells are not exhausted T cells. a Treg cell treatment did not promote the expression of exhaustion markers in senescent CD4+ T cells during the senescence development. Anti-CD3-pre-activated naive CD4+ T cells were co-cultured with nTreg or CD4+CD25- effector T cells (control) for 3 days, and then expression markers on treated T cells were determined by flow cytometry analyses. b Naive CD4+ T cells treated with CD4+CD25hiFoxP3+ Treg cells produced high levels of multiple cytokines, including IL-1β, IL-2, IL-6, IL-8, IL-10, IFN-γ, and TNF. mRNA expression levels of each cytokine were determined by the real-time PCR analyses. The expression level was normalized to GAPDH expression and adjusted to the levels in naive CD4+ T cells. Data are means ± SD from three representative naive CD4+ T cells. *p < 0.05 and **p < 0.01 compared with the CD4+CD25− treatment group determined by paired t test
Fig. 6 Senescent T cells induced by human Treg cells are not exhausted T cells. a Treg cell treatment did not promote the expression of exhaustion markers in senescent CD4+ T cells during the senescence development. Anti-CD3-pre-activated naive CD4+ T cells were co-cultured with nTreg or CD4+CD25- effector T cells (control) for 3 days, and then expression markers on treated T cells were determined by flow cytometry analyses. b Naive CD4+ T cells treated with CD4+CD25hiFoxP3+ Treg cells produced high levels of multiple cytokines, including IL-1β, IL-2, IL-6, IL-8, IL-10, IFN-γ, and TNF. mRNA expression levels of each cytokine were determined by the real-time PCR analyses. The expression level was normalized to GAPDH expression and adjusted to the levels in naive CD4+ T cells. Data are means ± SD from three representative naive CD4+ T cells. *p < 0.05 and **p < 0.01 compared with the CD4+CD25− treatment group determined by paired t testCC BY · PubMed Central
Fig. 7 The gene signature of Treg-induced senescent T cells is different from anergic T cells. a Transcriptome analyses of T-cell anergy-associated genes in naive CD8+ T cells after treatment with or without CD4+CD25hiFoxP3+ Treg cells. Gene alterations were normalized in log2 expression levels and divided into three groups based on the gene expression patterns compared with those in anergic T cells. Genes listed in Group 1 are significantly downregulated during the process of Treg-induced senescence, but reported to be upregulated in anergic T cells. Genes listed in group 2 were significantly upregulated in Treg-induced senescent T cells, but reported to be downregulated in anergic T cells. Genes listed in Group 3 have a consistent expression trend between Treg-induced senescent T cells and anergic T cells. b Different expression pattern of selected anergy-associated genes in inomycin-induced anergic and Treg-induced senescent CD4+ T cells. Relative mRNA expression levels of each gene in T cells were determined by real-time PCR with specific primers, and normalized to GAPDH expression. Data shown are mean ± SD from three independent experiments
Fig. 7 The gene signature of Treg-induced senescent T cells is different from anergic T cells. a Transcriptome analyses of T-cell anergy-associated genes in naive CD8+ T cells after treatment with or without CD4+CD25hiFoxP3+ Treg cells. Gene alterations were normalized in log2 expression levels and divided into three groups based on the gene expression patterns compared with those in anergic T cells. Genes listed in Group 1 are significantly downregulated during the process of Treg-induced senescence, but reported to be upregulated in anergic T cells. Genes listed in group 2 were significantly upregulated in Treg-induced senescent T cells, but reported to be downregulated in anergic T cells. Genes listed in Group 3 have a consistent expression trend between Treg-induced senescent T cells and anergic T cells. b Different expression pattern of selected anergy-associated genes in inomycin-induced anergic and Treg-induced senescent CD4+ T cells. Relative mRNA expression levels of each gene in T cells were determined by real-time PCR with specific primers, and normalized to GAPDH expression. Data shown are mean ± SD from three independent experimentsCC BY · PubMed Central
Fig. 8 Reversal of Treg-induced T-cell senescence by blockage of ATM and STAT signaling in vivo. Pretreatment of naive T cells with ATM inhibitor or STAT signaling inhibitors before co-injection with CD4+CD25hiFoxP3+ Treg cells can significantly block the induction of senescence and reverse the suppressive activity in transferred naive CD8+ T cells in NSG mice. Anti-CD3 activated naive CD8+ T cells (5 × 106 per mouse) were pretreated with the ATM inhibitor KU55933, or STAT1/3 inhibitors MTA or S3I-201 for 24 h, before co-transfer with CD4+CD25hiFoxP3+ Treg ( 2 × 106 per mouse) into NSG mice. The transferred human CD8+ T cells in different organs, including blood, lymph nodes (LN), and spleens (SP) were isolated at 12 days post injection for subsequent SA-β-Gal staining (in a and b), CD28 analysis by flow cytometry (in c), and suppressive activity with the 3H-thymidine incorporation assays (in d and e). *p < 0.05 and **p < 0.01, compared with the medium only group using the ANOVA analysis
Fig. 8 Reversal of Treg-induced T-cell senescence by blockage of ATM and STAT signaling in vivo. Pretreatment of naive T cells with ATM inhibitor or STAT signaling inhibitors before co-injection with CD4+CD25hiFoxP3+ Treg cells can significantly block the induction of senescence and reverse the suppressive activity in transferred naive CD8+ T cells in NSG mice. Anti-CD3 activated naive CD8+ T cells (5 × 106 per mouse) were pretreated with the ATM inhibitor KU55933, or STAT1/3 inhibitors MTA or S3I-201 for 24 h, before co-transfer with CD4+CD25hiFoxP3+ Treg ( 2 × 106 per mouse) into NSG mice. The transferred human CD8+ T cells in different organs, including blood, lymph nodes (LN), and spleens (SP) were isolated at 12 days post injection for subsequent SA-β-Gal staining (in a and b), CD28 analysis by flow cytometry (in c), and suppressive activity with the 3H-thymidine incorporation assays (in d and e). *p < 0.05 and **p < 0.01, compared with the medium only group using the ANOVA analysisCC BY · PubMed Central

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Metadata

Authors
Liu, X., Mo, W., Ye, J., Li, L., Zhang, Y., Hsueh, E. C., Hoft, D. F., & Peng, G.
Affiliations
Saint Louis University (US)
Corresponding author
Peng, Guangyong
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-01-16
Volume
9
Issue
1
Pages
249-249
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-02689-5
PMC
PMC5770447
OpenAlex
W2782893319
Cited by
224
References
64
Citations by year
2026: 17 · 2025: 40 · 2024: 39 · 2023: 16 · 2022: 30 · 2021: 32 · 2020: 28 · 2019: 13 · 2018: 9
FWCI
8.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American Cancer Society (RSG‐10‐160‐01‐LIB)
  • Melanoma Research Alliance
  • Washington University in St. Louis
  • National Institutes of Health (AI097852)
  • National Cancer Institute (R01CA184379)
  • National Institute of Allergy and Infectious Diseases (R21AI094478, R21AI097852)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
regulatory T cells, effector T cells, metabolic competition, DNA damage, ERK signaling, p38 MAPK signaling, STAT1, STAT3, DNA damage response, T cell exhaustion, anergy, adoptive T cell therapy, cancer immunotherapy, chronic infection
MeSH terms
DNA Damage, Glucose, Humans, Immunotherapy, Cellular Senescence, MAP Kinase Signaling System, T-Lymphocytes, Regulatory, STAT1 Transcription Factor, STAT3 Transcription Factor

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