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- Title
Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue.
- Authors
Martinez, Hunter A.; Koliesnik, Ievgen; Kaber, Gernot; Reid, Jacqueline K.; Nagy, Nadine; Barlow, Graham; Falk, Ben A.; Medina, Carlos O.; Hargil, Aviv; Zihsler, Svenja; Vlodavsky, Israel; Li, Jin-Ping; Pérez-Cruz, Magdiel; Tang, Sai-Wen; Meyer, Everett H.; Wrenshall, Lucile E.; Lord, James D.; Garcia, K. Christopher; Palmer, Theo D.; Steinman, Lawrence
- 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. Regulatory T cell (Treg) maintenance and function require IL-2, yet this cytokine is only present in low levels in vivo. In this study, the authors demonstrate that that Treg use heparanase to access IL-2 bound to heparan sulfate proteoglycans in the extracellular matrix of inflamed brain tissue in mice.
- Subjects
REGULATORY T cells; EXTRACELLULAR matrix; T cells; HEPARANASE; HEPARAN sulfate proteoglycans; HEPARAN sulfate; T cell receptors
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-45012-9