Abstract
In the current study, we investigated the nature and role of CD44 variant isoforms involved in endothelial cell (EC) injury and tumor cell cytotoxicity mediated by IL-2-activated killer (LAK) cells. Treatment of CD44 wild-type lymphocytes with IL-2 led to increased gene expression of CD44 v6 and v7 variant isoforms and to significant induction of vascular leak syndrome (VLS). CD44v6-v7 knockout (KO) and CD44v7 KO mice showed markedly reduced levels of IL-2-induced VLS. The decreased VLS in CD44v6-v7 KO and CD44v7 KO mice did not result from differential activation and expansion of CD8+ T cells, NK, and NK-T cells or from altered degree of perivascular lymphocytic infiltration in the lungs. LAK cells from CD44v7 KO mice showed a significant decrease in their ability to adhere to and mediate lysis of EC but not lysis of P815 tumor cells in vitro. CD44v7-mediated lysis of EC by LAK cells was dependent on the activity of phosphatidylinositol 3-kinase and tyrosine kinases. Interestingly, IL-2-activated LAK cells expressing CD44hi but not CD44lo were responsible for EC lysis. Furthermore, lysis of EC targets could be blocked by addition of soluble or enzymatic cleavage of CD44v6-v7-binding glycosaminoglycans. Finally, anti-CD44v7 mAbs caused a significant reduction in the adherence to and killing of EC and led to suppression of IL-2-induced VLS. Together, this study suggests that the expression of CD44v7 on LAK cells plays a specific role in EC injury and that it may be possible to reduce EC injury but not tumor cell killing by specifically targeting CD44v7.
Highlights
Endothelial cell (EC)1 injury is a widely occurring pathological condition seen during a variety of infections, autoimmunity, transplantation, and graft-versus-host disease and follow
Up-regulation of CD44v7 and CD44v6-v7 Variant Isoforms after IL-2 Treatment in Vivo—To determine whether IL-2 treatment led to the differential regulation of CD44 variant isoform expression, spleen cells from CD44 WT mice injected with IL-2 or PBS, as described under “Materials and Methods,” were harvested on day 4 and analyzed for the expression of various CD44 isoforms
The results showed that treatment with IL-2 in vivo led to the expression of a number of CD44 variant isoforms (Fig. 1)
Summary
Endothelial cell (EC) injury is a widely occurring pathological condition seen during a variety of infections, autoimmunity, transplantation, and graft-versus-host disease and follow-. Initial studies from our laboratory examining the role of CD44 in IL-2-induced VLS revealed that the induction of VLS in CD44 KO mice was significantly reduced when compared with CD44 wild-type (WT) mice [10]. Together, these observations suggested that activation through CD44 can enhance the effector functions of T lymphocytes and NK cells and that this may lead to the increased EC injury leading to VLS as well as effective killing of tumor cells. In addition to CD44s, a number of larger CD44 isoforms, ranging in size from 80 to 250 kDa, develop as a result of alternative splicing of variant exons [27]. These primers amplify CD44 isoforms containing alternatively spliced exons, but the standard form is of lower molecular weight and more abundant, and is preferentially amplified by PCR
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