Aberrant expression of adhesion molecules by Sézary cells: Functional consequences under physiologic shear stress conditions

Abstract

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 TCRVβ17+. Malignant T cell adhesion molecule abnormalities included an 80% downregulation of LFA-1 compared with normal controls and no detectable expression of α4 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-α activated dermal microvascular endothelial cells compared with normal CD4+ memory T cells. Cutaneous lymphocyte-associated antigen expression was detected in ∼25% of malignant T cells in the peripheral blood, but was substantially less than this in TCRVβ17+ 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.