FOXP3+ Regulatory T Cells Use Heparanase To Access IL-2 Bound to ECM in Inflamed Tissues

Hunter A. Martinez; Ievgen Koliesnik; Gernot Kaber; Nadine Nagy; Graham Barlow; Ben A. Falk; Jacqueline K. Reid; Carlos O. Medina; Aviv Hargil; Israel Vlodavsky; Jin-ping Li; Magdiel Perez-Cruz; Sai-Wen Tang; Everett H. Meyer; Lucile E. Wrenshall; James D. Lord; K. Christopher Garcia; Theo D. Palmer; Lawrence Steinman; Gerald T. Nepom; Thomas N. Wight; Paul L. Bollyky; Hedwich F. Kuipers

FOXP3+ Regulatory T Cells Use Heparanase To Access IL-2 Bound to ECM in Inflamed Tissues

Hunter A. Martinez, Ievgen Koliesnik, Gernot Kaber, Nadine Nagy, Graham Barlow, Ben A. Falk, Jacqueline K. Reid, Carlos O. Medina, Aviv Hargil, Israel Vlodavsky, Jin-ping Li, Magdiel Perez-Cruz, Sai-Wen Tang, Everett H. Meyer, Lucile E. Wrenshall, James D. Lord, K. Christopher Garcia, Theo D. Palmer, Lawrence Steinman, Gerald T. NepomThomas N. Wight, Paul L. Bollyky, Hedwich F. Kuipers

Neuroscience, Cell Biology, and Physiology (NCBP)

Research output: Contribution to journal › Article

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. ### Competing Interest Statement The authors have declared no competing interest.

Original language	American English
Pages (from-to)	2023.02.26.529772
Journal	bioRxiv (revisions under review at Nature Communications)
State	Published - 2023

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Martinez, H. A., Koliesnik, I., Kaber, G., Nagy, N., Barlow, G., Falk, B. A., Reid, J. K., Medina, C. O., Hargil, A., Vlodavsky, I., Li, J., Perez-Cruz, M., Tang, S.-W., Meyer, E. H., Wrenshall, L. E., Lord, J. D., Garcia, K. C., Palmer, T. D., Steinman, L., ... Kuipers, H. F. (2023). FOXP3+ Regulatory T Cells Use Heparanase To Access IL-2 Bound to ECM in Inflamed Tissues. bioRxiv (revisions under review at Nature Communications), 2023.02.26.529772.

Martinez, HA, Koliesnik, I, Kaber, G, Nagy, N, Barlow, G, Falk, BA, Reid, JK, Medina, CO, Hargil, A, Vlodavsky, I, Li, J, Perez-Cruz, M, Tang, S-W, Meyer, EH, Wrenshall, LE, Lord, JD, Garcia, KC, Palmer, TD, Steinman, L, Nepom, GT, Wight, TN, Bollyky, PL & Kuipers, HF 2023, 'FOXP3+ Regulatory T Cells Use Heparanase To Access IL-2 Bound to ECM in Inflamed Tissues', bioRxiv (revisions under review at Nature Communications), pp. 2023.02.26.529772.

@article{adc4c0af2e7d422d88de45f089d6e1dc,

title = "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. \#\#\# Competing Interest Statement The authors have declared no competing interest.",

author = "Martinez, \{Hunter A.\} and Ievgen Koliesnik and Gernot Kaber and Nadine Nagy and Graham Barlow and Falk, \{Ben A.\} and Reid, \{Jacqueline K.\} and Medina, \{Carlos O.\} and Aviv Hargil and Israel Vlodavsky and Jin-ping Li and Magdiel Perez-Cruz and Sai-Wen Tang and Meyer, \{Everett H.\} and Wrenshall, \{Lucile E.\} and Lord, \{James D.\} and Garcia, \{K. Christopher\} and Palmer, \{Theo D.\} and Lawrence Steinman and Nepom, \{Gerald T.\} and Wight, \{Thomas N.\} and Bollyky, \{Paul L.\} and Kuipers, \{Hedwich F.\}",

year = "2023",

language = "American English",

pages = "2023.02.26.529772",

journal = "bioRxiv (revisions under review at Nature Communications)",

}

TY - JOUR

T1 - FOXP3+ Regulatory T Cells Use Heparanase To Access IL-2 Bound to ECM in Inflamed Tissues

AU - Martinez, Hunter A.

AU - Koliesnik, Ievgen

AU - Kaber, Gernot

AU - Nagy, Nadine

AU - Barlow, Graham

AU - Falk, Ben A.

AU - Reid, Jacqueline K.

AU - Medina, Carlos O.

AU - Hargil, Aviv

AU - Vlodavsky, Israel

AU - Li, Jin-ping

AU - Perez-Cruz, Magdiel

AU - Tang, Sai-Wen

AU - Meyer, Everett H.

AU - Wrenshall, Lucile E.

AU - Lord, James D.

AU - Garcia, K. Christopher

AU - Palmer, Theo D.

AU - Steinman, Lawrence

AU - Nepom, Gerald T.

AU - Wight, Thomas N.

AU - Bollyky, Paul L.

AU - Kuipers, Hedwich F.

PY - 2023

Y1 - 2023

N2 - 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. ### Competing Interest Statement The authors have declared no competing interest.

AB - 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. ### Competing Interest Statement The authors have declared no competing interest.

UR - https://www.biorxiv.org/content/10.1101/2023.02.26.529772v1 https://www.biorxiv.org/content/10.1101/2023.02.26.529772v1.abstract

UR - https://www.mendeley.com/catalogue/5780ae5e-a984-3a95-938a-0e06057a330b/

M3 - Article

SP - 2023.02.26.529772

JO - bioRxiv (revisions under review at Nature Communications)

JF - bioRxiv (revisions under review at Nature Communications)

ER -

FOXP3+ Regulatory T Cells Use Heparanase To Access IL-2 Bound to ECM in Inflamed Tissues

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