Aberrant expression of adhesion molecules by Sézary cells: functional consequences under physiologic shear stress conditions.
Although aberrations in adhesion molecule expression by lymphoma cells have been reported, the functional consequences of these changes are unclear. Herein, we report a patient with Sézary syndrome whose malignant peripheral blood T cells were TCRVbeta17+. Malignant T cell adhesion molecule abnormalities included an 80% downregulation of LFA-1 compared with normal controls and no detectable expression of alpha4 integrin. Under shear stress conditions, malignant T cells failed to arrest on recombinant ICAM-1 in the presence of chemokines and displayed an 80% decrease in the ability to arrest on TNF-alpha activated dermal microvascular endothelial cells compared with normal CD4+ memory T cells. Cutaneous lymphocyte-associated antigen expression was detected in approximately 25% of malignant T cells in the peripheral blood, but was substantially less than this in TCRVbeta17+ T cells in the dermis. By contrast, > 95% of malignant T cells in peripheral blood expressed L-selectin (CD62L), and L-selectin ligand was detected in dermal blood vessels at affected skin sites. Compared with normal CD4+, malignant T cells attached and rolled 6-fold more efficiently on L-selectin ligand (p < 0.0001). Thus, despite aberrant expression of LFA-1 and functional defects in the ability to arrest on activated endothelial cells, malignant T cells in this patient entered skin and produced significant clinical disease. We propose a mechanism by which the upregulated expression of L-selectin and L-selectin ligands may partially compensate for altered LFA-1 function.
Dermatology Branch, National Cancer Institute, Bethesda, Maryland 20892-1908, USA. hwangs@mail.nih.gov
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D000368:Aged; D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000494:pharmacology; D019041:L-Selectin / Q000378:metabolism; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008833:Microcirculation; D019707:Receptors, Chemokine / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012751:Sezary Syndrome / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012867:Skin / Q000098:blood supply; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013314:Stress, Mechanical; D013601:T-Lymphocytes / Q000502:physiology
D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin