Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion
Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabol...
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| Published in | Nature immunology Vol. 22; no. 2; pp. 205 - 215 |
|---|---|
| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.02.2021
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1529-2908 1529-2916 1529-2916 |
| DOI | 10.1038/s41590-020-00834-9 |
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| Abstract | Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8
+
T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell–intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates.
Delgoffe and colleagues show that continuous TCR signaling and hypoxia increase Blimp-1, which suppresses PGC-1α-dependent mitochondrial reprogramming and increases reactive oxygen species generation. Such conditions promote T cell exhaustion. |
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| AbstractList | Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8+ T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell-intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates.Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8+ T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell-intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates. Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8+ T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell–intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates.Delgoffe and colleagues show that continuous TCR signaling and hypoxia increase Blimp-1, which suppresses PGC-1α-dependent mitochondrial reprogramming and increases reactive oxygen species generation. Such conditions promote T cell exhaustion. Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8.sup.+ T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1[alpha]-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell-intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates. Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8.sup.+ T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1[alpha]-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell-intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates. Delgoffe and colleagues show that continuous TCR signaling and hypoxia increase Blimp-1, which suppresses PGC-1[alpha]-dependent mitochondrial reprogramming and increases reactive oxygen species generation. Such conditions promote T cell exhaustion. Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8 + T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell–intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates. Delgoffe and colleagues show that continuous TCR signaling and hypoxia increase Blimp-1, which suppresses PGC-1α-dependent mitochondrial reprogramming and increases reactive oxygen species generation. Such conditions promote T cell exhaustion. Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8 T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell-intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates. Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic, and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized metabolic stress alters their responses to other signals, specifically persistent antigenic stimulation. In vitro , while CD8 + T cells experiencing continuous stimulation or hypoxia alone differentiate into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of ROS, sufficient to promote exhausted-like states, in part through phosphatase inhibition and consequent NFAT activity. Reducing T cell-intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates. |
| Audience | Academic |
| Author | Wang, Yiyang DePeaux, Kristin Rittenhouse, Natalie L. Poholek, Amanda C. Scharping, Nicole E. Rivadeneira, Dayana B. Peralta, Ronal Vignali, Paolo D. A. Wang, Yupeng Delgoffe, Greg M. Ford, B. Rhodes Menk, Ashley V. |
| AuthorAffiliation | 3 School of Medicine, Tsinghua University, Beijing, China 2 Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh 1 Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh |
| AuthorAffiliation_xml | – name: 2 Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh – name: 1 Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh – name: 3 School of Medicine, Tsinghua University, Beijing, China |
| Author_xml | – sequence: 1 givenname: Nicole E. orcidid: 0000-0001-9373-4617 surname: Scharping fullname: Scharping, Nicole E. organization: Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh – sequence: 2 givenname: Dayana B. surname: Rivadeneira fullname: Rivadeneira, Dayana B. organization: Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh – sequence: 3 givenname: Ashley V. surname: Menk fullname: Menk, Ashley V. organization: Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh – sequence: 4 givenname: Paolo D. A. surname: Vignali fullname: Vignali, Paolo D. A. organization: Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh – sequence: 5 givenname: B. Rhodes surname: Ford fullname: Ford, B. Rhodes organization: Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh – sequence: 6 givenname: Natalie L. surname: Rittenhouse fullname: Rittenhouse, Natalie L. organization: Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh – sequence: 7 givenname: Ronal surname: Peralta fullname: Peralta, Ronal organization: Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh – sequence: 8 givenname: Yiyang surname: Wang fullname: Wang, Yiyang organization: School of Medicine, Tsinghua University – sequence: 9 givenname: Yupeng surname: Wang fullname: Wang, Yupeng organization: School of Medicine, Tsinghua University – sequence: 10 givenname: Kristin orcidid: 0000-0001-8460-727X surname: DePeaux fullname: DePeaux, Kristin organization: Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh – sequence: 11 givenname: Amanda C. surname: Poholek fullname: Poholek, Amanda C. organization: Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh – sequence: 12 givenname: Greg M. orcidid: 0000-0002-2957-8135 surname: Delgoffe fullname: Delgoffe, Greg M. email: gdelgoffe@pitt.edu organization: Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33398183$$D View this record in MEDLINE/PubMed |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 AUTHOR CONTRIBUTIONS N.E.S. designed and performed experiments, analyzed data, and helped write the manuscript, D.B.R., A.V.M., and P.D.A.V. designed and performed experiments, and analyzed data. B.R.F and N.L.R. analyzed transcriptomic data. R.P. imaged microscopy experiments. Yiyang W. cloned overexpression plasmids. Yupeng W. aided Rho0 experiments. K.D. performed critical mouse experiments. A.C.P. oversaw bioinformatics research and provided crucial insight into Blimp-1-deficient experiments. G.M.D. conceived of, oversaw, and directed the research, performed initial experiments, analyzed data, obtained research funding, and wrote the manuscript. these authors contributed equally |
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| Snippet | Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics.... Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic, and metabolic characteristics.... |
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| SubjectTerms | 631/250/1619/554/1834/1269 631/250/2152/569/2495 631/250/2502 631/250/580 Animals Biomedical and Life Sciences Biomedicine CD8 antigen CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell differentiation Cell Line, Tumor Cell metabolism Coculture Techniques Energy Metabolism Epigenetics Female Health aspects HEK293 Cells Humans Hypoxia Immunological research Immunology Immunotherapy Infectious Diseases Lymphocyte Activation Lymphocytes Lymphocytes, Tumor-Infiltrating - immunology Lymphocytes, Tumor-Infiltrating - metabolism Male Melanoma, Experimental - genetics Melanoma, Experimental - immunology Melanoma, Experimental - metabolism Melanoma, Experimental - pathology Metabolism Mice Mice, Inbred C57BL Mice, Transgenic Mitochondria Mitochondria - immunology Mitochondria - metabolism NF-AT protein Oxidative stress Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism Physiological aspects Positive Regulatory Domain I-Binding Factor 1 - genetics Positive Regulatory Domain I-Binding Factor 1 - metabolism Reactive oxygen species Reactive Oxygen Species - metabolism Signal Transduction T cell receptors T cells Transcription factors Tumor Hypoxia Tumor Microenvironment |
| Title | Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion |
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