FOXP3⁺regulatory T cells use heparanase to access IL-2 bound to ECM in inflamed tissues

Abstract

FOXP3+ regulatory T cells (Treg) depend on exogenous IL-2 for their survival and function, but circulating levels of IL-2 are low, making it unclear how Treg access this critical resource in vivo. 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 the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their tolerogenic function in vivo. Together, these data identify novel roles for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity.

Spatiotemporally programming cytokine immunotherapies through protein engineering

“…This temporal regulation could be viewed as a feature subject to natural selection, limiting systemic exposure to cytokines from their local expression site. For example, IL‐2 is sequestered to some extent by the local extracellular matrix (ECM) after inflammation for subsequent access by Tregs 21,22 . However, in the therapeutic context, this rapid clearance following intravenous administration necessitates high and repeated dosing to overcome the minutes‐long half‐life 4 .…”

“…ECM‐based retention is a promising strategy for anchoring cytokines due to the overexpression of, for example, collagen in solid tumors 113,114 . Furthermore, this strategy is actually biomimetic, as numerous cytokines (e.g., IL‐2, 22 IFNɣ, 115 and IL‐12 116 ) exhibit strong ECM interactions that keep their endogenous effects localized. Momin et al reported on a collagen‐anchoring platform that leverages these intratumoral collagen reserves for enhanced cytokine retention 24 .…”

“…For example, IL-2 is sequestered to some extent by the local extracellular matrix (ECM) after inflammation for subsequent access by Tregs. 21,22 However, in the therapeutic context, this rapid clearance following intravenous administration necessitates high and repeated dosing to overcome the minutes-long half-life. 4 To address this, many preclinical studies, including ours, have used Fc-cytokine or albumincytokine fusions.…”