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FOXP3+ regulatory T cells use heparanase to access IL-2 bound to ECM in inflamed tissues. bioRxiv : the preprint server for biology Martinez, H. A., Koliesnik, I., Kaber, G., Reid, J. K., Nagy, N., Barlow, G., Falk, B. A., Medina, C. O., Hargil, A., Vlodavsky, I., Li, J. P., Pérez-Cruz, M., Tang, S. W., Meyer, E. H., Wrenshall, L. E., Lord, J. D., Garcia, K. C., Palmer, T. D., Steinman, L., Nepom, G. T., Wight, T. N., Bollyky, P. L., Kuipers, H. F. 2023

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.

View details for DOI 10.1101/2023.02.26.529772

View details for PubMedID 36909599

View details for PubMedCentralID PMC10002643