학술논문
Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue
Document Type
article
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
Source
Nature Communications, Vol 15, Iss 1, Pp 1-15 (2024)
Subject
Language
English
ISSN
2041-1723
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.