Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue.

Autor: Martinez HA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Koliesnik I; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Kaber G; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Reid JK; Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada., Nagy N; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Barlow G; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Falk BA; Matrix Biology Program, Benaroya Research Institute, Seattle, WA, USA., Medina CO; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Hargil A; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Zihsler S; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Vlodavsky I; Technion Integrated Cancer Center, Technion, Haifa, Israel., Li JP; Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden., Pérez-Cruz M; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Tang SW; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Meyer EH; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Wrenshall LE; Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA., Lord JD; Translational Research Program, Benaroya Research Institute, Seattle, WA, USA., Garcia KC; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Palmer TD; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA., Steinman L; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Nepom GT; Immune Tolerance Network, Benaroya Research Institute, Seattle, WA, USA., Wight TN; Matrix Biology Program, Benaroya Research Institute, Seattle, WA, USA., Bollyky PL; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Kuipers HF; Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. hedwich.kuipers@ucalgary.ca.; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada. hedwich.kuipers@ucalgary.ca.; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada. hedwich.kuipers@ucalgary.ca.; Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Canada. hedwich.kuipers@ucalgary.ca.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Feb 20; Vol. 15 (1), pp. 1564. Date of Electronic Publication: 2024 Feb 20.
DOI: 10.1038/s41467-024-45012-9
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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