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

Nat Commun. 2024 Feb 20;15(1):1564. 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.

MeSH terms

  • Animals
  • Encephalomyelitis, Autoimmune, Experimental*
  • Extracellular Matrix / metabolism
  • Glucuronidase / genetics
  • Glucuronidase / metabolism
  • Heparitin Sulfate / metabolism
  • Humans
  • Interleukin-2 / metabolism
  • Mice
  • T-Lymphocytes, Regulatory*


  • heparanase
  • Interleukin-2
  • Glucuronidase
  • Heparitin Sulfate