ArticleJournal of immunology (Baltimore, Md. : 1950)2013
Serine protease inhibitor 6 plays a critical role in protecting murine granzyme B-producing regulatory T cells.
Article in Journal of immunology (Baltimore, Md. : 1950), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Proteomics-based approach reveals the involvement of spliceosomal components SF3B and SerpinB9 in dermatofibrosarcoma protuberans.Orphanet journal of rare diseases · 2026Article
- Regulatory T cells in axial spondyloarthritis.Communications biology · 2026Review
- The pro-tumorigenic roles of granzyme B: mechanisms and therapeutic implications.Frontiers in immunology · 2025Review
- The biological function of Serpinb9 and Serpinb9-based therapy.Frontiers in immunology · 2024Review
- Review
- DecreasedJournal of immunology research · 2022Article
- Cytolytic CD4Frontiers in immunology · 2022Review
- mTORC1 Inhibition Protects Human Regulatory T Cells From Granzyme-B-Induced Apoptosis.Frontiers in immunology · 2022Article
- Sertoli Cell Immune Regulation: A Double-Edged Sword.Frontiers in immunology · 2022Review
- Identification of methylation signatures associated with CAR T cell in B-cell acute lymphoblastic leukemia and non-hodgkin's lymphoma.Frontiers in oncology · 2022Article
- Article
- Intrahepatic TFrontiers in pharmacology · 2020Review
- Molecular and functional heterogeneity of IL-10-producing CD4Nature communications · 2018Article
- Host-Derived Serine Protease Inhibitor 6 Provides Granzyme B-Independent Protection of Intestinal Epithelial Cells in Murine Graft-versus-Host Disease.Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation · 2018Article
- Human regulatory T cells undergo self-inflicted damage via granzyme pathways upon activation.JCI insight · 2017Article
- A pro-survival role for the intracellular granzyme B inhibitor Serpinb9 in natural killer cells during poxvirus infection.Immunology and cell biology · 2017Article
- Novel Application of Localized Nanodelivery of Anti-Interleukin-6 Protects Organ Transplant From Ischemia-Reperfusion Injuries.American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · 2017Article
- Cytotoxic CD4 T Cells-Friend or Foe during Viral Infection?Frontiers in immunology · 2017Review
- Regulatory and activated effector T cells in chronic hepatitis C virus: Relation to autoimmunity.World journal of hepatology · 2016Article
- A Novel Serpin Regulatory Mechanism: SerpinB9 IS REVERSIBLY INHIBITED BY VICINAL DISULFIDE BOND FORMATION IN THE REACTIVE CENTER LOOP.The Journal of biological chemistry · 2016Article
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Authors and funding
16 authors.
Funding
Abstract
Regulatory T cells (Tregs) play a pivotal role in the maintenance of immune tolerance and hold great promise as cell therapy for a variety of immune-mediated diseases. However, the cellular mechanisms that regulate Treg maintenance and homeostasis have yet to be fully explored. Although Tregs express granzyme-B (GrB) to suppress effector T cells via direct killing, the mechanisms by which they protect themselves from GrB-mediated self-inflicted damage are unknown. To our knowledge, we show for the first time that both induced Tregs and natural Tregs (nTregs) increase their intracellular expression of GrB and its endogenous inhibitor, serine protease inhibitor 6 (Spi6) upon activation. Subcellular fractionation and measurement of GrB activity in the cytoplasm of Tregs show that activated Spi6(-/-) Tregs had significantly higher cytoplasmic GrB activity. We observed an increase in GrB-mediated apoptosis in Spi6(-/-) nTregs and impaired suppression of alloreactive T cells in vitro. Spi6(-/-) Tregs were rescued from apoptosis by the addition of a GrB inhibitor (Z-AAD-CMK) in vitro. Furthermore, adoptive transfer experiments showed that Spi6(-/-) nTregs were less effective than wild type nTregs in suppressing graft-versus-host disease because of their impaired survival, as shown in our in vivo bioluminescence imaging. Finally, Spi6-deficient recipients rejected MHC class II-mismatch heart allografts at a much faster rate and showed a higher rate of apoptosis among Tregs, as compared with wild type recipients. To our knowledge, our data demonstrate, for the first time, a novel role for Spi6 in Treg homeostasis by protecting activated Tregs from GrB-mediated injury. These data could have significant clinical implications for Treg-based therapy in immune-mediated diseases.
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