5 results on '"Martin W. LaFleur"'
Search Results
2. T Cell Activation Depends on Extracellular Alanine
- Author
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Noga Ron-Harel, Jonathan M. Ghergurovich, Giulia Notarangelo, Martin W. LaFleur, Yoshiki Tsubosaka, Arlene H. Sharpe, Joshua D. Rabinowitz, and Marcia C. Haigis
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Summary: T cell stimulation is metabolically demanding. To exit quiescence, T cells rely on environmental nutrients, including glucose and the amino acids glutamine, leucine, serine, and arginine. The expression of transporters for these nutrients is tightly regulated and required for T cell activation. In contrast to these amino acids, which are essential or require multi-step biosynthesis, alanine can be made from pyruvate by a single transamination. Here, we show that extracellular alanine is nevertheless required for efficient exit from quiescence during naive T cell activation and memory T cell restimulation. Alanine deprivation leads to metabolic and functional impairments. Mechanistically, this vulnerability reflects the low expression of alanine aminotransferase, the enzyme required for interconverting pyruvate and alanine, whereas activated T cells instead induce alanine transporters. Stable isotope tracing reveals that alanine is not catabolized but instead supports protein synthesis. Thus, T cells depend on exogenous alanine for protein synthesis and normal activation. : In health, T lymphocytes are in a resting state. However, stimulation with their cognate antigen induces massive growth and proliferation. Ron-Harel et al. demonstrate that T cells rely on extracellular alanine for activation. Consumed alanine is used primarily for protein synthesis, and alanine deprivation inhibits T cell metabolism and effector functions. Keywords: T cells, T cell activation, protein synthesis, metabolism, alanine
- Published
- 2019
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3. T Cell Activation Depends on Extracellular Alanine
- Author
-
Martin W. LaFleur, Marcia C. Haigis, Jonathan M. Ghergurovich, Yoshiki Tsubosaka, Arlene H. Sharpe, Noga Ron-Harel, Giulia Notarangelo, and Joshua D. Rabinowitz
- Subjects
Alanine ,chemistry.chemical_classification ,Chemistry ,Transamination ,T-Lymphocytes ,Metabolism ,Lymphocyte Activation ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cell biology ,Amino acid ,Glutamine ,Serine ,chemistry.chemical_compound ,Mice ,Biosynthesis ,lcsh:Biology (General) ,Animals ,Leucine ,Immunologic Memory ,lcsh:QH301-705.5 - Abstract
Summary: T cell stimulation is metabolically demanding. To exit quiescence, T cells rely on environmental nutrients, including glucose and the amino acids glutamine, leucine, serine, and arginine. The expression of transporters for these nutrients is tightly regulated and required for T cell activation. In contrast to these amino acids, which are essential or require multi-step biosynthesis, alanine can be made from pyruvate by a single transamination. Here, we show that extracellular alanine is nevertheless required for efficient exit from quiescence during naive T cell activation and memory T cell restimulation. Alanine deprivation leads to metabolic and functional impairments. Mechanistically, this vulnerability reflects the low expression of alanine aminotransferase, the enzyme required for interconverting pyruvate and alanine, whereas activated T cells instead induce alanine transporters. Stable isotope tracing reveals that alanine is not catabolized but instead supports protein synthesis. Thus, T cells depend on exogenous alanine for protein synthesis and normal activation. : In health, T lymphocytes are in a resting state. However, stimulation with their cognate antigen induces massive growth and proliferation. Ron-Harel et al. demonstrate that T cells rely on extracellular alanine for activation. Consumed alanine is used primarily for protein synthesis, and alanine deprivation inhibits T cell metabolism and effector functions. Keywords: T cells, T cell activation, protein synthesis, metabolism, alanine
- Published
- 2019
4. PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity
- Author
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Kathleen A. McGuire, Arlene H. Sharpe, W. Nicholas Haining, Robert T. Manguso, Natalie B. Collins, Martin W. LaFleur, Vikram R. Juneja, and Gordon J. Freeman
- Subjects
0301 basic medicine ,Cytotoxicity, Immunologic ,Immunology ,Programmed Cell Death 1 Receptor ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,B7-H1 Antigen ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,PD-L1 ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Cytotoxicity ,Melanoma ,Research Articles ,Tumor microenvironment ,biology ,Chemistry ,Brief Definitive Report ,medicine.disease ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,Tumor Escape ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Colorectal Neoplasms ,CD8 - Abstract
Both tumor- and host-derived PD-L1 can play critical roles in immunosuppression; differences in tumor immunogenicity appear to underlie their relative contributions. Juneja et al. show that in immunogenic MC38 tumors, PD-L1 on tumor cells dominates in suppressing tumor immunity by inhibiting CD8 T cell cytotoxicity., It is unclear whether PD-L1 on tumor cells is sufficient for tumor immune evasion or simply correlates with an inflamed tumor microenvironment. We used three mouse tumor models sensitive to PD-1 blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity. MC38-derived PD-L1 potently inhibited CD8+ T cell cytotoxicity. Wild-type MC38 cells outcompeted PD-L1–deleted MC38 cells in vivo, demonstrating tumor PD-L1 confers a selective advantage. Thus, both tumor- and host-derived PD-L1 can play critical roles in immunosuppression. Differences in tumor immunogenicity appear to underlie their relative importance. Our findings establish reduced cytotoxicity as a key mechanism by which tumor PD-L1 suppresses antitumor immunity and demonstrate that tumor PD-L1 is not just a marker of suppressed antitumor immunity.
- Published
- 2017
5. The epigenetic landscape of T cell exhaustion
- Author
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Nir Yosef, W. Nicholas Haining, Debattama R. Sen, Damien C. Tully, Ulrike Gerdemann, Flavian D. Brown, Kathleen B. Yates, Pierre Tonnerre, James Kaminski, R. Anthony Barnitz, Nicole Frahm, Jernej Godec, Makoto Kurachi, Raymond T. Chung, Martin W. LaFleur, Georg M. Lauer, Todd M. Allen, Hsiao-Wei Tsao, and E. John Wherry
- Subjects
0301 basic medicine ,HIV Infections ,CD8-Positive T-Lymphocytes ,Inbred C57BL ,B7-H1 Antigen ,Mice ,0302 clinical medicine ,Gene expression ,Chronic ,Genetics ,Regulation of gene expression ,Gene Editing ,Multidisciplinary ,Hepatitis C ,Chromatin ,medicine.anatomical_structure ,Infectious Diseases ,030220 oncology & carcinogenesis ,Immunotherapy ,Infection ,Transcription ,Enhancer Elements ,General Science & Technology ,T cell ,1.1 Normal biological development and functioning ,Biology ,Lymphocytic Choriomeningitis ,complex mixtures ,Article ,03 medical and health sciences ,Genetic ,Underpinning research ,medicine ,Animals ,Humans ,Cell Lineage ,Epigenetics ,Enhancer ,Gene ,Animal ,SOXB1 Transcription Factors ,Prevention ,Human Genome ,030104 developmental biology ,Disease Models ,Chronic Disease ,T-Box Domain Proteins ,Immunologic Memory ,CD8 ,Epigenesis - Abstract
Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells.
- Published
- 2016
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