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

Author:

Martinez Hunter A.ORCID,Koliesnik IevgenORCID,Kaber GernotORCID,Reid Jacqueline K.,Nagy NadineORCID,Barlow GrahamORCID,Falk Ben A.,Medina Carlos O.,Hargil Aviv,Zihsler Svenja,Vlodavsky IsraelORCID,Li Jin-Ping,Pérez-Cruz Magdiel,Tang Sai-Wen,Meyer Everett H.,Wrenshall Lucile E.,Lord James D.,Garcia K. ChristopherORCID,Palmer Theo D.ORCID,Steinman LawrenceORCID,Nepom Gerald T.,Wight Thomas N.,Bollyky Paul L.ORCID,Kuipers Hedwich F.ORCID

Abstract

AbstractAlthough 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.

Publisher

Springer Science and Business Media LLC

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