Sézary syndrome cells overexpress syndecan-4 bearing distinct heparan sulfate moieties that suppress T-cell activation by binding DC-HIL and trapping TGF-beta on the cell surface.
Because syndecan-4 (SD-4) on effector and memory T cells inhibits T-cell activation by binding dendritic cell-associated heparan sulfate proteoglycan-integrin ligand (DC-HIL) on antigen presenting cells and because malignant cells of the cutaneous T-cell lymphoma (CTCL) subset, Sézary syndrome (SS), exhibit memory T-cell phenotype, we posited SS cells to express SD-4. Indeed, malignant T cells from patients with SS and from CTCL cell lines constitutively expressed SD-4 at high levels, in contrast to T cells from healthy volunteers and patients with other inflammatory skin diseases and to non-CTCL cell lines that did not. SS cells also bound to DC-HIL at a level higher than normal T cells activated in vitro, resulting in their inhibited proliferation to anti-CD3 antibody. SD-4 on SS cells also trapped transforming growth factor-β1 to their cell surface, enhancing their ability to inhibit activation of syngeneic and allogeneic normal T cells. All of these inhibitory properties were dependent on overexpression of distinct heparan sulfate (HS) moieties by SD-4 on SS cells. Finally, we showed toxin-conjugated DC-HIL to abrogate the ability of SS cells to proliferate in vitro. These findings indicate that SD-4 bearing distinct HS moieties plays a pathogenic role in SS and may be targeted for treatment.
Department of Dermatology, The University of Texas Southwestern Medical Center and Dermatology Section (Medical Service), Dallas Veterans Affairs Medical Center, Dallas, TX 75390-9069, USA.
Jin-Sung
JS
Chung
Lisa H
LH
Shiue
Madeleine
M
Duvic
Amit
A
Pandya
Ponciano D
PD
Cruz
Kiyoshi
K
Ariizumi
D000368:Aged; D000369:Aged, 80 and over; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D006497:Heparan Sulfate / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D016410:Lymphoma, T-Cell, Cutaneous / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology; D008875:Middle Aged; D011485:Protein Binding / Q000276:immunology / Q000502:physiology; D021381:Protein Transport; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D012751:Sezary Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053671:Syndecan-4 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D006497:Heparan Sulfate; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D053671:Syndecan-4; D016212:Transforming Growth Factor beta; C503042:GPNMB protein, human
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