ArticleBMC immunology2009
Induction of granzyme B expression in T-cell receptor/CD28-stimulated human regulatory T cells is suppressed by inhibitors of the PI3K-mTOR pathway.
Article in BMC immunology, 2009. 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, 43 citations in OpenAlex.
- Monoclonal antibodies targeting PCDH7 inhibit tumor growth and enhance immune responses inScience advances · 2026Article
- Automated GMP-compatible production of universal CAR Tregs for organ-targeted tolerance induction.Journal of translational medicine · 2025Article
- Tumor-priming CD8Experimental hematology & oncology · 2025Article
- Tolerogenic Therapies in Cardiac Transplantation.International journal of molecular sciences · 2025Review
- Granzyme B and melittin in cancer immunotherapy: molecular mechanisms and therapeutic perspectives in head and neck cancers.Frontiers in immunology · 2025Review
- Signaling pathways of marine-derived natural products on lung injury: from theFrontiers in pharmacology · 2025Review
- The immunotherapy era in ovarian clear cell carcinoma: current evidence and future perspective.Frontiers in immunology · 2025Review
- Targeting the immune microenvironment for ovarian cancer therapy.Frontiers in immunology · 2023Review
- Mucosal viral infection induces a regulatory T cell activation phenotype distinct from tissue residency in mouse and human tissues.Mucosal immunology · 2022Article
- Cytolytic CD4Frontiers in immunology · 2022Review
- mTORC1 Inhibition Protects Human Regulatory T Cells From Granzyme-B-Induced Apoptosis.Frontiers in immunology · 2022Article
- Interaction Networks Converging on Immunosuppressive Roles of Granzyme B: Special Niches Within the Tumor Microenvironment.Frontiers in immunology · 2021Review
- Review
- Article
- Chimeric antigen receptor costimulation domains modulate human regulatory T cell function.JCI insight · 2019Article
- IL-10 inducible CD8Cancer immunology, immunotherapy : CII · 2018Article
- Human regulatory T cells undergo self-inflicted damage via granzyme pathways upon activation.JCI insight · 2017Article
- Cytotoxic CD4 T Cells-Friend or Foe during Viral Infection?Frontiers in immunology · 2017Review
- Interleukin-4 Supports the Suppressive Immune Responses Elicited by Regulatory T Cells.Frontiers in immunology · 2017Article
- Tregs activated by bispecific antibodies: Killers or suppressors?Oncoimmunology · 2015Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundRegulatory T cells (Tregs) can employ a cell contact- and granzyme B-dependent mechanism to mediate suppression of bystander T and B cells. Murine studies indicate that granzyme B is involved in the Treg-mediated suppression of anti-tumor immunity in the tumor microenvironment and in the Treg-mediated maintenance of allograft survival. In spite of its central importance, a detailed study of granzyme B expression patterns in human Tregs has not been performed.
resultsOur data demonstrated that natural Tregs freshly isolated from the peripheral blood of normal adults lacked granzyme B expression. Tregs subjected to prolonged TCR and CD28 triggering, in the presence of IL-2, expressed high levels of granzyme B but CD3 stimulation alone or IL-2 treatment alone failed to induce granzyme B. Treatment of Tregs with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin or the PI3 kinase (PI3K) inhibitor LY294002 markedly suppressed granzyme B expression. However, neither rapamycin, as previously reported by others, nor LY294002 inhibited Treg proliferation or induced significant cell death in TCR/CD28/IL-2 stimulated cells. The proliferation rate of Tregs was markedly higher than that of CD4+ conventional T cells in the setting of rapamycin treatment. Tregs expanded by CD3/CD28/IL-2 stimulation without rapamycin demonstrated increased in vitro cytotoxic activity compared to Tregs expanded in the presence of rapamycin in both short term (6 hours) and long term (48 hours) cytotoxicity assays.
conclusionTCR/CD28 mediated activation of the PI3K-mTOR pathway is important for granyzme B expression but not proliferation in regulatory T cells. These findings may indicate that suppressive mechanisms other than granzyme B are utilized by rapamycin-expanded Tregs.
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