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

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 and Hedwich F. Kuipers ()
Additional contact information
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
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

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45012-9

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