Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue
Abstract Although FOXP3+ regulatory T cells (Treg) depend on IL-2 produced by other cells for their survival and function, the levels of IL-2 in inflamed tissue are low, making it unclear how Treg access this critical resource. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45012-9 |
| _version_ | 1827326772922810368 |
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| author | Hunter A. Martinez Ievgen Koliesnik Gernot Kaber Jacqueline K. Reid Nadine Nagy Graham Barlow Ben A. Falk Carlos O. Medina Aviv Hargil Svenja Zihsler Israel Vlodavsky Jin-Ping Li Magdiel Pérez-Cruz Sai-Wen Tang Everett H. Meyer Lucile E. Wrenshall James D. Lord K. Christopher Garcia Theo D. Palmer Lawrence Steinman Gerald T. Nepom Thomas N. Wight Paul L. Bollyky Hedwich F. Kuipers |
| author_facet | Hunter A. Martinez Ievgen Koliesnik Gernot Kaber Jacqueline K. Reid Nadine Nagy Graham Barlow Ben A. Falk Carlos O. Medina Aviv Hargil Svenja Zihsler Israel Vlodavsky Jin-Ping Li Magdiel Pérez-Cruz Sai-Wen Tang Everett H. Meyer Lucile E. Wrenshall James D. Lord K. Christopher Garcia Theo D. Palmer Lawrence Steinman Gerald T. Nepom Thomas N. Wight Paul L. Bollyky Hedwich F. Kuipers |
| author_sort | Hunter A. Martinez |
| collection | DOAJ |
| description | Abstract Although FOXP3+ regulatory T cells (Treg) depend on IL-2 produced by other cells for their survival and function, the levels of IL-2 in inflamed tissue are low, making it unclear how Treg access this critical resource. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed central nervous system tissue. HPSE expression distinguishes human and murine Treg from conventional T cells and is regulated by the availability of IL-2. HPSE-/- Treg have impaired stability and function in vivo, including in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing monoclonal antibody-directed chimeric antigen receptor (mAbCAR) Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their ability to suppress neuroinflammation in vivo. Together, these data identify a role for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity. |
| first_indexed | 2024-03-07T14:50:21Z |
| format | Article |
| id | doaj.art-378775d4b0fd41108905367cda2de0de |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:50:21Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-378775d4b0fd41108905367cda2de0de2024-03-05T19:44:00ZengNature PortfolioNature Communications2041-17232024-02-0115111510.1038/s41467-024-45012-9Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissueHunter A. Martinez0Ievgen Koliesnik1Gernot Kaber2Jacqueline K. Reid3Nadine Nagy4Graham Barlow5Ben A. Falk6Carlos O. Medina7Aviv Hargil8Svenja Zihsler9Israel Vlodavsky10Jin-Ping Li11Magdiel Pérez-Cruz12Sai-Wen Tang13Everett H. Meyer14Lucile E. Wrenshall15James D. Lord16K. Christopher Garcia17Theo D. Palmer18Lawrence Steinman19Gerald T. Nepom20Thomas N. Wight21Paul L. Bollyky22Hedwich F. Kuipers23Department of Medicine, Stanford University School of MedicineDepartment of Medicine, Stanford University School of MedicineDepartment of Medicine, Stanford University School of MedicineDepartment of Clinical Neurosciences, Cumming School of Medicine, University of CalgaryDepartment of Medicine, Stanford University School of MedicineDepartment of Medicine, Stanford University School of MedicineMatrix Biology Program, Benaroya Research InstituteDepartment of Medicine, Stanford University School of MedicineDepartment of Medicine, Stanford University School of MedicineDepartment of Medicine, Stanford University School of MedicineTechnion Integrated Cancer Center, TechnionDepartment of Medical Biochemistry and Microbiology, Uppsala UniversityDepartment of Medicine, Stanford University School of MedicineDepartment of Medicine, Stanford University School of MedicineDepartment of Medicine, Stanford University School of MedicineDepartment of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine, Wright State UniversityTranslational Research Program, Benaroya Research InstituteDepartment of Molecular and Cellular Physiology, Stanford University School of MedicineDepartment of Neurosurgery, Stanford University School of MedicineDepartment of Neurology and Neurological Sciences, Stanford University School of MedicineImmune Tolerance Network, Benaroya Research InstituteMatrix Biology Program, Benaroya Research InstituteDepartment of Medicine, Stanford University School of MedicineDepartment of Clinical Neurosciences, Cumming School of Medicine, University of CalgaryAbstract Although FOXP3+ regulatory T cells (Treg) depend on IL-2 produced by other cells for their survival and function, the levels of IL-2 in inflamed tissue are low, making it unclear how Treg access this critical resource. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed central nervous system tissue. HPSE expression distinguishes human and murine Treg from conventional T cells and is regulated by the availability of IL-2. HPSE-/- Treg have impaired stability and function in vivo, including in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing monoclonal antibody-directed chimeric antigen receptor (mAbCAR) Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their ability to suppress neuroinflammation in vivo. Together, these data identify a role for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity.https://doi.org/10.1038/s41467-024-45012-9 |
| spellingShingle | Hunter A. Martinez Ievgen Koliesnik Gernot Kaber Jacqueline K. Reid Nadine Nagy Graham Barlow Ben A. Falk Carlos O. Medina Aviv Hargil Svenja Zihsler Israel Vlodavsky Jin-Ping Li Magdiel Pérez-Cruz Sai-Wen Tang Everett H. Meyer Lucile E. Wrenshall James D. Lord K. Christopher Garcia Theo D. Palmer Lawrence Steinman Gerald T. Nepom Thomas N. Wight Paul L. Bollyky Hedwich F. Kuipers Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue Nature Communications |
| title | Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue |
| title_full | Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue |
| title_fullStr | Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue |
| title_full_unstemmed | Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue |
| title_short | Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue |
| title_sort | regulatory t cells use heparanase to access il 2 bound to extracellular matrix in inflamed tissue |
| url | https://doi.org/10.1038/s41467-024-45012-9 |
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