Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue.
Hunter A MartinezIevgen KoliesnikGernot KaberJacqueline K ReidNadine NagyGraham L BarlowBen A FalkCarlos O MedinaAviv HargilSvenja ZihslerIsrael VlodavskyJin-Ping LiMagdiel Pérez-CruzSai-Wen TangEverett H MeyerLucile E WrenshallJames D LordK Christopher GarciaTheo D PalmerLawrence SteinmanGerald T NepomThomas N WightPaul L BollykyHedwich F KuipersPublished in: Nature communications (2024)
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.
Keyphrases
- regulatory t cells
- extracellular matrix
- multiple sclerosis
- dendritic cells
- mouse model
- monoclonal antibody
- poor prognosis
- endothelial cells
- traumatic brain injury
- inflammatory response
- cell cycle arrest
- stem cells
- cell death
- oxidative stress
- blood brain barrier
- electronic health record
- deep learning
- smoking cessation
- binding protein
- endoplasmic reticulum stress