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Regulatory T cells ...
Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue
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- Martinez, Hunter A. (author)
- Stanford Univ, Sch Med, Dept Med, Stanford, CA USA.
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- Koliesnik, Ievgen (author)
- Stanford Univ, Sch Med, Dept Med, Stanford, CA USA.
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- Kaber, Gernot (author)
- Stanford Univ, Sch Med, Dept Med, Stanford, CA USA.
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- Reid, Jacqueline K. (author)
- Univ Calgary, Cumming Sch Med, Dept Clin Neurosci, Calgary, AB, Canada.;Univ Calgary, Cumming Sch Med, Hotchkiss Brain Inst, Calgary, AB, Canada.;Univ Calgary, Cumming Sch Med, Snyder Inst Chron Dis, Calgary, AB, Canada.
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- Nagy, Nadine (author)
- Stanford Univ, Sch Med, Dept Med, Stanford, CA USA.
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- Barlow, Graham (author)
- Stanford Univ, Sch Med, Dept Med, Stanford, CA USA.
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- Falk, Ben A. (author)
- Benaroya Res Inst, Matrix Biol Program, Seattle, WA USA.
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- Medina, Carlos O. (author)
- Stanford Univ, Sch Med, Dept Med, Stanford, CA USA.
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- Hargil, Aviv (author)
- Stanford Univ, Sch Med, Dept Med, Stanford, CA USA.
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- Zihsler, Svenja (author)
- Stanford Univ, Sch Med, Dept Med, Stanford, CA USA.
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- Vlodavsky, Israel (author)
- Technion, Technion Integrated Canc Ctr, Haifa, Israel.
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- Li, Jin-Ping (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Perez-Cruz, Magdiel (author)
- Stanford Univ, Sch Med, Dept Med, Stanford, CA USA.
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- Tang, Sai-Wen (author)
- Stanford Univ, Sch Med, Dept Med, Stanford, CA USA.
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- Meyer, Everett H. (author)
- Stanford Univ, Sch Med, Dept Med, Stanford, CA USA.
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- Wrenshall, Lucile E. (author)
- Wright State Univ, Boonshoft Sch Med, Dept Neurosci Cell Biol & Physiol, Dayton, OH 45459 USA.
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- Lord, James D. (author)
- Benaroya Res Inst, Translat Res Program, Seattle, WA USA.
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- Garcia, K. Christopher (author)
- Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.
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- Palmer, Theo D. (author)
- Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA USA.
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- Steinman, Lawrence (author)
- Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA USA.
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- Nepom, Gerald T. (author)
- Immune Tolerance Network, Benaroya Res Inst, Seattle, WA USA.
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- Wight, Thomas N. (author)
- Benaroya Res Inst, Matrix Biol Program, Seattle, WA USA.
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- Bollyky, Paul L. (author)
- Stanford Univ, Sch Med, Dept Med, Stanford, CA USA.
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- Kuipers, Hedwich F. (author)
- Univ Calgary, Cumming Sch Med, Dept Clin Neurosci, Calgary, AB, Canada.;Univ Calgary, Cumming Sch Med, Hotchkiss Brain Inst, Calgary, AB, Canada.;Univ Calgary, Cumming Sch Med, Snyder Inst Chron Dis, Calgary, AB, Canada.;Univ Calgary, Cumming Sch Med, Dept Cell Biol & Anat, Calgary, AB, Canada.
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Stanford Univ, Sch Med, Dept Med, Stanford, CA USA Univ Calgary, Cumming Sch Med, Dept Clin Neurosci, Calgary, AB, Canada.;Univ Calgary, Cumming Sch Med, Hotchkiss Brain Inst, Calgary, AB, Canada.;Univ Calgary, Cumming Sch Med, Snyder Inst Chron Dis, Calgary, AB, Canada. (creator_code:org_t)
- Springer Nature, 2024
- 2024
- English.
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Abstract
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- Although 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. Regulatory T cell (Treg) maintenance and function require IL-2, yet this cytokine is only present in low levels in vivo. In this study, the authors demonstrate that that Treg use heparanase to access IL-2 bound to heparan sulfate proteoglycans in the extracellular matrix of inflamed brain tissue in mice.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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- By the author/editor
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Martinez, Hunter ...
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Koliesnik, Ievge ...
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Kaber, Gernot
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Reid, Jacqueline ...
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Nagy, Nadine
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Barlow, Graham
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show more...
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Falk, Ben A.
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Medina, Carlos O ...
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Hargil, Aviv
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Zihsler, Svenja
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Vlodavsky, Israe ...
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Li, Jin-Ping
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Perez-Cruz, Magd ...
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Tang, Sai-Wen
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Meyer, Everett H ...
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Wrenshall, Lucil ...
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Lord, James D.
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Garcia, K. Chris ...
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Palmer, Theo D.
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Steinman, Lawren ...
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Nepom, Gerald T.
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Wight, Thomas N.
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Bollyky, Paul L.
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Kuipers, Hedwich ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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Nature Communica ...
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Uppsala University