The CD44 variant isoforms CD44v6 and CD44v7 are expressed by distinct leukocyte subpopulations and exert non-overlapping functional activities

Abstract

We have described recently that anti-CD44s, anti-CD44v6 and anti-CD44v7 interfere with delayed-type hypersensitivity (DTH) reactions. Yet, TNBS-induced colitis can be cured only by anti-CD44v7. To clarify the mechanisms underlying the divergent functional activities of CD44v6 and CD44v7 we explored their contribution to lymphocyte activation in vivo and in vitro. CD44v6 and CD44v7 are distinctly expressed on subpopulations of activated lymphocytes. Expression of CD44v6 is mainly restricted to T cell blasts. CD44v7 has been detected on CD4(+) cells, B cells and monocytes. Mitogenic and antigenic stimulation of lymphocytes in vitro was impaired in the presence of anti-CD44v6 and anti-CD44v7. Accordingly, anti-CD44v6 and anti-CD44v7 mitigated the DTH reaction in 2,4-dinitro-1-fluorobenzene-sensitized and challenged mice. However, the seemingly similar effects of CD44v6- and CD44v7-specific antibodies resulted from different activities. Anti-CD44v6 treatment led to a down-regulation of IL-2 and IFN-gamma production predominantly by CD8(+) cells. In anti-CD44v7-treated mice expression of IL-12 was decreased. Elevated levels of IL-10 accompanied this reduction. The latter resulted from an anti-CD44v7-mediated blockade of interactions between CD4(+) cells and monocytes as well as an active triggering of B cells. Thus, anti-CD44v6 and anti-CD44v7 interfere with lymphocyte activation at very specific points. CD44v6 functions predominantly at the T cell level. CD44v7 influences production of proinflammatory cytokines by B cells as well as an interaction between CD4(+) cells and antigen-presenting cells. As CD44 isoforms do not differ in their intracytoplasmatic tail, the distinct activities must result from expression on different leukocyte subsets and interactions with distinct ligands.

CD44 variant–specific antibodies trigger hemopoiesis by selective release of cytokines from bone marrow macrophages

“…[34][35][36] Furthermore, the production of cytokines in lymphocytes seems to be mediated by CD44. 37 Interestingly, the induction of the synthesis of the cytokine M-CSF has also been observed in peripheral macrophages upon treatment with CD44-specific antibodies, 38 although it should be noted that the increase in cytokine protein was only marginal.…”

Role of CD44 and Its v7 Isoform in Staphylococcal Enterotoxin B-Induced Toxic Shock: CD44 Deficiency on Hepatic Mononuclear Cells Leads to Reduced Activation-Induced Apoptosis That Results in Increased Liver Damage

“…Although the product of a single gene, CD44 is expressed as multiple isoforms that result from alternatively spliced mRNA species and posttranslational modifications (3,17,52). These isoforms are expressed during different stages of activation and by different effector cells (44). Therefore, it is possible that different CD44 isoforms may have unique and sometimes opposite roles in the regulation of apoptosis.…”

The Ruthenium Complex cis-(Dichloro)Tetraammineruthenium(III) Chloride Presents Immune Stimulatory Activity on Human Peripheral Blood Mononuclear Cells

“…In fact, previous studies sustained this hypothesis showing that NAMI-A upregulates CD44 expression manly in T cells [31], and the CD44 molecule is able to induce proliferation and IL-2 production by T cells [52,53]. The CD44 isoform CD44v6 is expressed preferentially in T cells and only expressed transiently during the early phase of T cell activation [54]. Recently, it was demonstrated that mouse thymoma EL4 transfected with CD44v6 (EL4-v6) in the absence of any stimulus proliferated at an over tenfold higher rate than untransfected cells, displayed upregulated expression of CD69, CD25, and IL-2, and were protected from apoptosis by CD44v6 cross-linking [55].…”