6 results on '"Creg J, Workman"'
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2. Competition for Active TGFβ Cytokine Allows for Selective Retention of Antigen-Specific Tissue- Resident Memory T Cells in the Epidermal Niche
- Author
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Dario A. A. Vignali, David W. Griggs, Daniel H. Kaplan, Haiyue Li, Creg J. Workman, Yi Yang, Toshiro Hirai, Yukari Zenke, David Masopust, Breanna Anh Thu Nguyen, Harinder Singh, Laurent Bartholin, Jacinto S. De La Cruz Diaz, Virendra K. Chaudhri, and Paul Yifan Zhou
- Subjects
Keratinocytes ,0301 basic medicine ,Receptors, Antigen, T-Cell, alpha-beta ,medicine.medical_treatment ,Immunology ,T-Cell Antigen Receptor Specificity ,CD8-Positive T-Lymphocytes ,Biology ,Binding, Competitive ,T-Lymphocytes, Regulatory ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Transforming Growth Factor beta ,medicine ,Bystander effect ,Animals ,Immunology and Allergy ,Autocrine signalling ,Lymph node ,integumentary system ,Epidermis (botany) ,Bystander Effect ,Clone Cells ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Infectious Diseases ,Cytokine ,medicine.anatomical_structure ,Cellular Microenvironment ,Organ Specificity ,030220 oncology & carcinogenesis ,Epidermis ,Immunologic Memory ,CD8 ,Signal Transduction ,Transforming growth factor - Abstract
Summary Following antigen-driven expansion in lymph node, transforming growth factor-β (TGFβ) is required for differentiation of skin-recruited CD8+ T cell effectors into epidermal resident memory T (Trm) cells and their epidermal persistence. We found that the source of TGFβ -supporting Trm cells was autocrine. In addition, antigen-specific Trm cells that encountered cognate antigen in the skin, and bystander Trm cells that did not, both displayed long-term persistence in the epidermis under steady-state conditions. However, when the active-TGFβ was limited or when new T cell clones were recruited into the epidermis, antigen-specific Trm cells were more efficiently retained than bystander Trm cells. Genetically enforced TGFβR signaling allowed bystander Trm cells to persist in the epidermis as efficiently as antigen-specific Trm cells in both contexts. Thus, competition between T cells for active TGFβ represents an unappreciated selective pressure that promotes the accumulation and persistence of antigen-specific Trm cells in the epidermal niche.
- Published
- 2021
3. Interleukin-35 Limits Anti-Tumor Immunity
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Meghan E. Turnis, Hiroshi Yano, Lawrence P. Andrews, Amy J. Beres, Deepali V. Sawant, Creg J. Workman, Dario A. A. Vignali, Greg M. Delgoffe, Andrea L. Szymczak-Workman, and Peter Vogel
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0301 basic medicine ,Skin Neoplasms ,LAG3 ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Immunology ,Melanoma, Experimental ,chemical and pharmacologic phenomena ,Cell Growth Processes ,T-Lymphocytes, Regulatory ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigens, CD ,Immunity ,Cell Line, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Immunology and Allergy ,Antibodies, Blocking ,Hepatitis A Virus Cellular Receptor 2 ,Cell Proliferation ,Mice, Knockout ,Tumor microenvironment ,biology ,Antitumor immunity ,Effector ,Interleukins ,Lymphocyte Activation Gene 3 Protein ,Tumor Burden ,Mice, Inbred C57BL ,030104 developmental biology ,Infectious Diseases ,Cytokine ,030220 oncology & carcinogenesis ,Interleukin 35 ,biology.protein ,Receptors, Virus ,Antibody ,Immunologic Memory - Abstract
Summary Regulatory T (Treg) cells pose a major barrier to effective anti-tumor immunity. Although Treg cell depletion enhances tumor rejection, the ensuing autoimmune sequelae limits its utility in the clinic and highlights the need for limiting Treg cell activity within the tumor microenvironment. Interleukin-35 (IL-35) is a Treg cell-secreted cytokine that inhibits T cell proliferation and function. Using an IL-35 reporter mouse, we observed substantial enrichment of IL-35 + Treg cells in tumors. Neutralization with an IL-35-specific antibody or Treg cell-restricted deletion of IL-35 production limited tumor growth in multiple murine models of human cancer. Limiting intratumoral IL-35 enhanced T cell proliferation, effector function, antigen-specific responses, and long-term T cell memory. Treg cell-derived IL-35 promoted the expression of multiple inhibitory receptors (PD1, TIM3, LAG3), thereby facilitating intratumoral T cell exhaustion. These findings reveal previously unappreciated roles for IL-35 in limiting anti-tumor immunity and contributing to T cell dysfunction in the tumor microenvironment.
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- 2016
4. Treg Cells Promote the SREBP1-Dependent Metabolic Fitness of Tumor-Promoting Macrophages via Repression of CD8
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Chang, Liu, Maria, Chikina, Rahul, Deshpande, Ashley V, Menk, Ting, Wang, Tracy, Tabib, Erin A, Brunazzi, Kate M, Vignali, Ming, Sun, Donna B, Stolz, Robert A, Lafyatis, Wei, Chen, Greg M, Delgoffe, Creg J, Workman, Stacy G, Wendell, and Dario A A, Vignali
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Mice, Knockout ,Carcinogenesis ,Macrophages ,Fatty Acids ,Melanoma, Experimental ,chemical and pharmacologic phenomena ,Cell Differentiation ,Forkhead Transcription Factors ,Neoplasms, Experimental ,CD8-Positive T-Lymphocytes ,T-Lymphocytes, Regulatory ,Neuropilin-1 ,Article ,Mice, Inbred C57BL ,Interferon-gamma ,Mice ,Th2 Cells ,Tumor Microenvironment ,Animals ,Sterol Regulatory Element Binding Protein 1 ,Melanoma ,Immune Evasion - Abstract
Regulatory T (Treg) cells are crucial for immune homeostasis but they also contribute to tumor immune evasion by promoting a suppressive tumor microenvironment (TME). Mice with Treg cell-restricted Neuropilin 1 deficiency show tumor resistance while maintaining peripheral immune homeostasis, thereby providing a controlled system to interrogate the impact of intratumoral Treg cells on the TME. Using this and other genetic models, we showed that Treg cells shaped the transcriptional landscape across multiple tumor-infiltrating immune cell types. Treg cells suppressed CD8(+) T cell secretion of interferon-γ (IFNγ), which would otherwise block the activation of sterol regulatory elementbinding protein 1 (SREBP1)-mediated fatty acid synthesis in immunosuppressive (M2-like) tumor-associated macrophages (TAMs). Thus, Treg cells indirectly but selectively sustained M2-like TAM metabolic fitness, mitochondrial integrity and survival. SREBP1 inhibition augmented the efficacy of immune checkpoint blockade, suggesting that targeting Treg cells or their modulation of lipid metabolism in M2-like TAMs could improve cancer immunotherapy.
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- 2018
5. Treg Cells Promote the SREBP1-Dependent Metabolic Fitness of Tumor-Promoting Macrophages via Repression of CD8+ T Cell-Derived Interferon-γ
- Author
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Greg M. Delgoffe, Maria Chikina, Chang Liu, Tracy Tabib, Ashley V. Menk, Creg J. Workman, Stacy G. Wendell, Rahul Deshpande, Donna B. Stolz, Ming Sun, Erin A. Brunazzi, Robert Lafyatis, Dario A. A. Vignali, Kate M. Vignali, Ting Wang, and Wei Chen
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0301 basic medicine ,Cell type ,Tumor microenvironment ,medicine.medical_treatment ,Immunology ,chemical and pharmacologic phenomena ,Biology ,Immune checkpoint ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Infectious Diseases ,Immune system ,Cancer immunotherapy ,030220 oncology & carcinogenesis ,Genetic model ,medicine ,Cancer research ,Immunology and Allergy ,Cytotoxic T cell ,CD8 - Abstract
Summary Regulatory T (Treg) cells are crucial for immune homeostasis, but they also contribute to tumor immune evasion by promoting a suppressive tumor microenvironment (TME). Mice with Treg cell-restricted Neuropilin-1 deficiency show tumor resistance while maintaining peripheral immune homeostasis, thereby providing a controlled system to interrogate the impact of intratumoral Treg cells on the TME. Using this and other genetic models, we showed that Treg cells shaped the transcriptional landscape across multiple tumor-infiltrating immune cell types. Treg cells suppressed CD8+ T cell secretion of interferon-γ (IFNγ), which would otherwise block the activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated fatty acid synthesis in immunosuppressive (M2-like) tumor-associated macrophages (TAMs). Thus, Treg cells indirectly but selectively sustained M2-like TAM metabolic fitness, mitochondrial integrity, and survival. SREBP1 inhibition augmented the efficacy of immune checkpoint blockade, suggesting that targeting Treg cells or their modulation of lipid metabolism in M2-like TAMs could improve cancer immunotherapy.
- Published
- 2019
6. Role of LAG-3 in Regulatory T Cells
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Sowmya Ravi, Drew M. Pardoll, Dario A. A. Vignali, Edward L. Hipkiss, Jonathan D. Powell, Ching Tai Huang, Charles G. Drake, Dallas B. Flies, Xiaoyu Pan, Hyam I. Levitsky, Jeanne Kowalski, Gang Zhou, Aimee L. Marson, and Creg J. Workman
- Subjects
Lung Diseases ,Vasculitis ,Adoptive cell transfer ,LAG3 ,Regulatory T cell ,T-Lymphocytes ,Immunology ,Receptors, Antigen, T-Cell ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Mice ,03 medical and health sciences ,Interleukin 21 ,0302 clinical medicine ,Antigens, CD ,Transduction, Genetic ,Immune Tolerance ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,IL-2 receptor ,Oligonucleotide Array Sequence Analysis ,030304 developmental biology ,0303 health sciences ,MHC class II ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Effector ,Gene Expression Profiling ,Cell Differentiation ,Receptors, Interleukin-2 ,hemic and immune systems ,Adoptive Transfer ,Immunohistochemistry ,Lymphocyte Activation Gene 3 Protein ,3. Good health ,Cell biology ,Hemagglutinins ,Infectious Diseases ,medicine.anatomical_structure ,CD4 Antigens ,biology.protein ,Immunologic Memory ,Biomarkers ,030215 immunology - Abstract
Regulatory T cells (Tregs) limit autoimmunity but also attenuate the magnitude of antipathogen and antitumor immunity. Understanding the mechanism of Treg function and therapeutic manipulation of Tregs in vivo requires identification of Treg-selective receptors. A comparative analysis of gene expression arrays from antigen-specific CD4(+) T cells differentiating to either an effector/memory or a regulatory phenotype revealed Treg-selective expression of LAG-3, a CD4-related molecule that binds MHC class II. Antibodies to LAG-3 inhibit suppression by induced Tregs both in vitro and in vivo. Natural CD4(+)CD25(+) Tregs express LAG-3 upon activation, which is significantly enhanced in the presence of effector cells, whereas CD4(+)CD25(+) Tregs from LAG-3(-/-) mice exhibit reduced regulatory activity. Lastly, ectopic expression of LAG-3 on CD4(+) T cells significantly reduces their proliferative capacity and confers on them suppressor activity toward effector T cells. We propose that LAG-3 marks regulatory T cell populations and contributes to their suppressor activity.
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