Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38378682.
- Also identified by DOI 10.1038/s41467-024-45012-9 and PMC identifier 10879116.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Although FOXP3<sup>+</sup> 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<sup>-/-</sup> 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.
Medical subject headings
- T-Lymphocytes, Regulatory
- Encephalomyelitis, Autoimmune, Experimental