Autoimmune neurologic diseases
Foxp3+ regulatory T cells (Treg) depend on exogenous IL-2 for function and homeostasis. However, circulating levels of IL-2 are generally low, making it unclear how Treg access this resource in vivo. We report that IL-2 is sequestered by heparan sulfate (HS) moieties within inflammatory lesions in the experimental autoimmune encephalomyelitis model of multiple sclerosis. HS-bound IL-2 supports Treg homeostasis more potently than soluble IL-2, but accessing this sequestered IL-2 requires heparanase (HPSE). Both murine and human Treg express HPSE more abundantly than conventional CD4+ T cells. Accordingly, Hpse-/- Treg are compromised in their ability to utilize HS-bound IL-2 and display impaired homeostasis and suppressive function in vitro and in vivo. Moreover, CAR-Treg engineered to express HPSE show enhanced phenotypic stability in vitro and in vivo compared to conventional CAR-Treg. These data indicate that HPSE and HS-bound IL-2 contribute to Foxp3+ Treg homeostasis and function and provide new avenues for improving Treg-based cell therapy of autoimmunity.