Transendothelial migration of lymphocytes in chronic lymphocytic leukaemia is impaired and involved down-regulation of both L-selectin and CD23

Abstract

Summary.Chronic lymphocytic leukaemia (B-CLL) is characterized by a progressive accumulation of B lymphocytes in blood and bone marrow and high concentrations of soluble CD23 and L-selectin are found in the serum of these patients. In this study lymphocytes from normal subjects and patients with B-CLL were allowed to undergo transendothelial migration across confluent layers of human umbilical vein endothelial cells. Lymphocytes in B-CLL samples showed an impaired capacity to migrate while the minor proportion of normal T cells was enriched by a mean of 2·5-fold in the transmigrated lymphocytes. In contrast, the ratio of B to T lymphocytes in normal preparations was unchanged in the transmigrated population. The expression of adhesion molecules on B-CLL lymphocytes before and after transendothelial migration was studied by flow cytometry which showed that 71 Ϯ 5% of L-selectin was lost from the surface of transmigrated lymphocytes. T and B cells from normal subjects also showed a major loss of L-selectin after transmigration. B-CLL lymphocytes and normal B cells expressed CD23 but this molecule was down-regulated following transendothelial migration, whereas the expression of VLA-4, ICAM-1, LFA-1 and CD44 was unchanged. Lymphocytes incubated with oxidized ATP, an irreversible inhibitor of P2Z/P2X7 purinoceptors, retained their capacity for transendothelial migration and showed the same loss of L-selectin as control leukaemic lymphocytes. Our results show that B-CLL lymphocytes have impaired ability for transendothelial migration compared to normal peripheral blood lymphocytes. Moreover, transendothelial migration involves a universal loss of L-selectin and CD23 from lymphocytes which suggests that the high serum levels of soluble L-selectin and CD23 observed in B-CLL may be generated by shedding during the process of transendothelial migration.

Expression of L-selectin and efficient binding to high endothelial venules do not modulate the dissemination potential of murine B-cell lymphoma

“…Similarly, lymphocyte activation by a variety of stimuli induces L-selectin shedding from the cell surface [12,23,25,33,34]. Moreover, transendothelial migration of leukocytes involves down-regulation of L-selectin [1,2,14]. Although there is a debate whether shedding of L-selectin is required for migration of neutrophils across endothelium [2,39], it appears that L-selectin shedding is a prerequisite for lymphocyte transendothelial migration [1,2].…”

“…Some malignant cells may express L-selectin that is not shed. Thus, it has been reported that L-selectin-positive chronic lymphocytic leukemia (CLL) cells bound to HEV at levels corresponding to the amount of L-selectin expressed on their surface, whereas L-selectin-negative CLL cells did not bind to HEV [14]. However, among L-selectin-positive CLL cells, some did not shed the homing receptor following exposure to PMA, while others shed it in a time course that was slower than in normal lymphocytes, suggesting that the signaling pathway for shedding may be less active in some malignant cells [14].…”

“…Thus, it has been reported that L-selectin-positive chronic lymphocytic leukemia (CLL) cells bound to HEV at levels corresponding to the amount of L-selectin expressed on their surface, whereas L-selectin-negative CLL cells did not bind to HEV [14]. However, among L-selectin-positive CLL cells, some did not shed the homing receptor following exposure to PMA, while others shed it in a time course that was slower than in normal lymphocytes, suggesting that the signaling pathway for shedding may be less active in some malignant cells [14]. It therefore appears that, in spite of the correlation between expression of L-selectin and the capacity of malignant cells to bind to HEV, high expression of the homing receptor may not generally predict the capacity of the cells to disseminate into lymph nodes.…”

Clipping, shedding and RIPping keep immunity on cue

“…Blocking ADAM17 activity by both synthetic and natural MMP inhibitors causes the arrest of lymphocyte migration across high endothelial venules [28]. B-cell chronic lymphocytic leukemia (B-CLL) lymphocytes have impaired transendothelial migration compared to normal peripheral blood lymphocytes [29]. Moreover, transendothelial migration of B-CLLs involves the universal loss of L-selectin and CD23 from their cell surface.…”

Laminin-332 (Laminin-5) is the major motility ligand for B cell chronic lymphocytic leukemia

“…Of note, α3-expressing B-CLL lymphocytes with the CD62L + CD54 + CD25 + CD40 + phenotype harbored at higher frequency a larger number of IgV H mutations (Degan et al, 2004a;Hamblin et al, 1999;Damle et al, 1999), as well as an IgV H mutational status consistent with antigen-driven selection Chang and Casali, 1994;Chen et al, 1999;Degan et al, 2004a;Lossos et al, 2000;Zucchetto et al, 2005). Noteworthy, CD62L, CD54, CD25 and CD40 correspond to surface components that are involved in the cross-talk between B-CLL lymphocytes with neighboring endothelial and/or T cells within the lymph node microenvironment (Chen et al, 1999;Lane et al, 1992;Poudrier and Owens, 1994;Gu et al, 2001;Mills and Cambier, 2003) and their expression is consistent with the fact that IgV H mutations usually occur as the result of T celldependent interactions during GC-maturation of B cells (Dorner et al, 1998). Findings reported in the present study, indicating the presence of a specific mesh of LM-332 fibrils in the context of marginal zones and/or follicle interspaces of normal reactive lymph nodes, corroborate this hypothesis.…”