ArticleJournal of immunology (Baltimore, Md. : 1950)2015
Nonapoptotic and extracellular activity of granzyme B mediates resistance to regulatory T cell (Treg) suppression by HLA-DR-CD25hiCD127lo Tregs in multiple sclerosis and in response to IL-6.
Article in Journal of immunology (Baltimore, Md. : 1950), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 49 citations in OpenAlex.
- Emerging roles of granzymes in neurodegeneration and neuroinflammation: mechanistic insights and therapeutic opportunities.Acta neuropathologica · 2026Review
- Metabolic reprogramming as a therapeutic target for modulating the Th17/Treg balance in autoimmune diseases: a comprehensive review.Frontiers in immunology · 2025Review
- The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases.Nature reviews. Immunology · 2024Review
- The Plasticity of Immune Cell Response Complicates Dissecting the Underlying Pathology of Multiple Sclerosis.Journal of immunology research · 2024Review
- Alpha-Synuclein-Specific Regulatory T Cells Ameliorate Parkinson's Disease Progression in Mice.International journal of molecular sciences · 2023Article
- Identification of key genes as potential diagnostic and therapeutic targets for comorbidity of myasthenia gravis and COVID-19.Frontiers in neurology · 2023Article
- Immune-microbiome interplay and its implications in neurodegenerative disorders.Metabolic brain disease · 2022Review
- Treg-Resistant Cytotoxic CD4International journal of molecular sciences · 2021Article
- Emerging patterns of regulatory T cell function in tuberculosis.Clinical and experimental immunology · 2020Review
- CD4 T cell-intrinsic role for the T helper 17 signature cytokine IL-17: Effector resistance to immune suppression.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo.Journal of autoimmunity · 2019Article
- Experimental Autoimmune Encephalomyelitis (EAE) as Animal Models of Multiple Sclerosis (MS).Cold Spring Harbor perspectives in medicine · 2018Review
- Engineered MBP-specific human Tregs ameliorate MOG-induced EAE through IL-2-triggered inhibition of effector T cells.Journal of autoimmunity · 2018Article
- Immunomodulatory function of Treg-derived exosomes is impaired in patients with relapsing-remitting multiple sclerosis.Immunologic research · 2018Article
- Effector T Cells in Multiple Sclerosis.Cold Spring Harbor perspectives in medicine · 2018Review
- CD28 between tolerance and autoimmunity: the side effects of animal models.F1000Research · 2018Review
- Phenotypic and functional complexity of brain-infiltrating T cells in Rasmussen encephalitis.Neurology(R) neuroimmunology & neuroinflammation · 2018Article
- Human IL-6RClinical immunology (Orlando, Fla.) · 2017Article
- From IgG Fusion Proteins to Engineered-Specific Human Regulatory T Cells: A Life of Tolerance.Frontiers in immunology · 2017Review
- Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression.Science translational medicine · 2016Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
In autoimmune patients, regulatory T cells (Tregs) are increasingly found to be unable to suppress patient-derived T cells, an outcome referred to as Treg resistance. In this study, we show that CD4 T cells from patients with multiple sclerosis resist suppression by patient-derived or healthy donor-derived ex vivo Tregs. Importantly, we report that granzyme B (GzmB) contributes to this Treg resistance via a novel, apoptosis-independent mechanism. We show that memory CD4(+)CD127(lo)FOXP3(+) Treg subsets do not express GzmB, whereas activated, nonregulatory CD4 T cells isolated from patients with multiple sclerosis express higher levels of GzmB than do cells from healthy donors. In contrast to the intracellular GzmB that mediates apoptosis, GzmB can be found in extracellular fluids where it is hypothesized to regulate other cellular processes. In this study, we show that providing extracellular GzmB strongly inhibits Treg suppression, without altering Treg viability. However, when GzmB and GzmB-specific inhibitor are both provided to the cocultures, Treg suppression occurs. Thus, these data suggest that a novel activity of extracellular GzmB is to regulate Treg suppression. Additionally, we find that the suppression-abrogating cytokine IL-6 augments GzmB expression by human CD4 T cells, and it inhibits Treg suppression via this nonapoptotic GzmB-mediated mechanism. Lastly, in examining the mechanism whereby GzmB inhibits Treg function, we show that extracellular GzmB reduces Treg expression of CD39 and programmed death ligand 1. Collectively, these data indicate that extracellular GzmB plays an unexpected, nonapoptotic role in regulating Treg suppression and suggest that inactivation of specifically the extracellular activity of GzmB may be an efficacious therapeutic in autoimmunity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.