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  • Besides the enhanced expression of


    Besides the enhanced expression of costimulatory and adhesion proteins, also the expression of the CD83 surface molecule is strongly enhanced during DC maturation (Banchereau and Steinman 1998; Banchereau et al. 2000). In fact, CD83 is a major cell surface marker for fully mature DC, as it can not be detected on DC precursors (Zhou and Tedder 1996). However, it should be noted that CD83 has been reported to be also expressed to some extent in B and T lymphocytes as well as in polymorph-nuclear neutrophiles (Zhou et al. 1992; Kozlow et al. 1993; Cramer et al. 2000; Iking-Konert et al. 2001; McKinsey et al. 2000). Human CD83 is a glycoprotein of about 45kDa and consists of 205 isoxsuprine sale (Kozlow et al. 1993; Zhou et al. 1992). Because of its structure it belongs to the immune globulin superfamily. According to the fact that CD83 shows strong activation during DC maturation, it was proposed that CD83 exhibit an important function during T cell activation (Lechmann et al., 2002a, Lechmann et al., 2002b). So far, the bona fide function of CD83 is not fully understood and a definite CD83 binding-ligand has not been identified yet (discussed in Lechmann et al., 2001). Nevertheless, experimental studies suggested an important regulatory function of CD83 in lymphocyte maturation, homeostasis and, particularly, in DC-mediated immune responses (for recent reviews see Prechtel and Steinkasserer 2007; Breloer and Fleischer 2008). It has been shown that the development of CD4+/CD8− thymocytes is disturbed in CD83-deficient knockout mice (Fujimoto et al. 2002). Furthermore, it has been demonstrated that application of a soluble CD83 variant leads to inhibition of DC-mediated T cell activation in an allogeneic mixed lymphocyte reaction (MLR) (Lechmann et al. 2001). Moreover, soluble CD83-IgG fusion protein exhibits immune suppressive features in vivo and application of soluble CD83 protein prevents experimental autoimmune encephalomyelitis in an appropriate animal model (Scholler et al. 2002; Zinser et al. 2004a). Importantly, endogenous soluble CD83 protein was detected in the supernatants of DC and B cells (Hock et al. 2001), suggesting a role of the membrane bound CD83-form in activation of T cell-mediated immune responses and of the soluble CD83-form in prevention of autoimmune disorders and induction of tolerance mechanisms. A series of former studies provided preliminary indirect evidence that the nucleo-cytoplasmic transport of mRNAs encoding CD83 may be specifically regulated in DC. For example, the cytoplasmic accumulation of a small subset of cellular transcripts, including CD83 mRNA, appears to depend on a functional CRM1 nuclear export pathway in activated T cells (Schütz et al. 2006). This finding was rather unexpected, since it is well established that the vast majority of cellular mRNAs are transported from the site of transcription, the cell nucleus, to the cytoplasmic site of protein synthesis via the unrelated Tap/NXF1 pathway (Izaurralde 2004; Erkmann isoxsuprine sale and Kutay 2004). The hypothesis that CRM1 may be operational in the regulation of CD83-specific mRNAs in DC is further supported by the previous studies that demonstrated that low molecular weight inhibitors of eukaryotic initiation factor 5A (eIF-5A) reduced CD83 expression and suppressed DC activity (Kruse et al. 2000; Zinser et al. 2004b; Hauber et al. 2005). Interestingly, eIF-5A has also been shown to be a cellular cofactor of the human immunodeficiency virus type 1 (HIV-1) Rev regulatory protein (Bevec et al. 1996; Hauber et al. 2005), which mediates the nuclear export of unspliced and incompletely spliced retroviral transcripts via the CRM1 pathway (for review see Pollard and Malim 1998).
    Materials and methods
    Discussion Dendritic cells have to mature to activate T cell-dependent immune responses (Banchereau and Steinman 1998; Banchereau et al. 2000; Mellman and Steinman 2001). An important part of this maturation process is the up-regulation of the expression of the surface protein CD83. It has been repeatedly shown that interference with CD83, for example by applying soluble CD83 variants, significantly impairs the capacity of DC to stimulate T cell proliferation (Lechmann et al. 2001; Scholler et al. 2002; Zinser et al. 2004a). In addition, CD83 knockdown by siRNA technologies also resulted in reduced DC-mediated T cell stimulation (Prechtel et al. 2007; Aerts-Toegaert et al. 2007). Our data presented here, demonstrating that inhibition of CD83 surface expression by the highly specific CRM1 inhibitor LMB interferes with the ability of DC to induce allogeneic T cell proliferation, may further support these observations. Clearly, the functional impairment of DC generated in presence of LMB can not be exclusively attributed to its indirect inhibition of CD83 expression. It is expected that also other transcripts are regulated in DC by the LMB target CRM1 and, that some of the products encoded by these messages are required for efficient DC function. Our data showing that LMB not only affects the cytoplasmic accumulation of CD83 mRNA, but also transcripts encoding CD80 and CD86 support this notion. Furthermore, this would also explain our observation that already a relatively low concentration of 1μM LMB abolishes DC-mediated T cell activation but only partially interferes with CD83 surface expression in the respective DC.