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

• Published in: Nature communications 2024-02, Vol.15 (1), p.1564-15, Article 1564
• Main 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, Nepom, Gerald T., Wight, Thomas N., Bollyky, Paul L., Kuipers, Hedwich F.
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/31; 14; 14/19; 38/77; 631/250/1619/554/1898/1271; 631/250/371; 64/60; Animal tissues; Animals; Autoimmunity; Central nervous system; Chimeric antigen receptors; Encephalomyelitis, Autoimmune, Experimental; Experimental allergic encephalomyelitis; Extracellular matrix; Extracellular Matrix - metabolism; Foxp3 protein; Glucuronidase - genetics; Glucuronidase - metabolism; Heparan sulfate; Heparan sulfate proteoglycans; Heparitin Sulfate - metabolism; Humanities and Social Sciences; Humans; Immunological tolerance; Immunoregulation; In vivo methods and tests; Inflammation; Interleukin 2; Interleukin-2 - metabolism; Lymphocytes; Lymphocytes T; Mice; Monoclonal antibodies; multidisciplinary; Multiple sclerosis; Nervous tissues; Proteoglycans; Science; Science (multidisciplinary); Sulfates; T-Lymphocytes, Regulatory
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45012-9

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 (T reg ) 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 T reg use heparanase to access IL-2 bound to heparan sulfate proteoglycans in the extracellular matrix of inflamed brain tissue in mice.