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

Author

Listed:
  • Hunter A. Martinez

    (Stanford University School of Medicine)

  • Ievgen Koliesnik

    (Stanford University School of Medicine)

  • Gernot Kaber

    (Stanford University School of Medicine)

  • Jacqueline K. Reid

    (University of Calgary
    University of Calgary
    University of Calgary)

  • Nadine Nagy

    (Stanford University School of Medicine)

  • Graham Barlow

    (Stanford University School of Medicine)

  • Ben A. Falk

    (Benaroya Research Institute)

  • Carlos O. Medina

    (Stanford University School of Medicine)

  • Aviv Hargil

    (Stanford University School of Medicine)

  • Svenja Zihsler

    (Stanford University School of Medicine)

  • Israel Vlodavsky

    (Technion)

  • Jin-Ping Li

    (Uppsala University)

  • Magdiel Pérez-Cruz

    (Stanford University School of Medicine)

  • Sai-Wen Tang

    (Stanford University School of Medicine)

  • Everett H. Meyer

    (Stanford University School of Medicine)

  • Lucile E. Wrenshall

    (Wright State University)

  • James D. Lord

    (Benaroya Research Institute)

  • K. Christopher Garcia

    (Stanford University School of Medicine)

  • Theo D. Palmer

    (Stanford University School of Medicine)

  • Lawrence Steinman

    (Stanford University School of Medicine)

  • Gerald T. Nepom

    (Benaroya Research Institute)

  • Thomas N. Wight

    (Benaroya Research Institute)

  • Paul L. Bollyky

    (Stanford University School of Medicine)

  • Hedwich F. Kuipers

    (University of Calgary
    University of Calgary
    University of Calgary
    University of Calgary)

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.

Suggested Citation

  • 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, 2024. "Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45012-9
    DOI: 10.1038/s41467-024-45012-9
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