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About CD83

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1. Dendritic cells: inducers of T-cell mediated immunity

2. Particular events during CD83 gene expression and mRNA processing

Chromosomal location of CD83 and promoter events
CD83 mRNA export from nucleus to cytoplasm

3. From mRNA to protein

Species and cell types that express CD83
The different forms of CD83

4. The different functions of soluble and membrane-bound CD83

Functions of membrane-bound CD83 (extra-thymic functions)
Intra-thymic functions of mCD83

5. The functions of soluble CD83 (sCD83)

Characterization of sCD83
Effects of sCD83 on DCs
Effects of sCD83 on T-cells

6. CD83 as a target for viral immune escape mechanisms

References

Dendritic cells: inducers of T-cell mediated immunity

Dendritic cells (DCs) are often referred to as ‘nature’s adjuvant’ because they are equipped with the unique ability to stimulate naïve CD4+ and CD8+ T-cells. Thus, specialized to activate helper and killer T-cells during the initiation of immune responses, they represent the most potent antigen presenting cells (APCs) of the human immune system known today. In order to induce specific T-cell mediated immune responses, they act as sentinels of the immune system and lie in wait in an immature state in almost all peripheral tissues. Immature DCs (iDCs) in the epidermis are known as Langerhans cells [8, 60, 91].

The contact of iDCs with various products of infectious agents and/or exposure to inflammatory stimuli [3, 16, 19] induces dramatic changes in DCs’ biology, regarding morphology [1, 17, 25, 86], migratory capability [30, 37, 72, 73], expression of surface molecules [81, 88] and function [8, 76, 91]. While iDCs are specialized to up-take and process antigens, mature DCs (mDCs) have developed the ability to migrate and ‘transfer’ their information to the areas of antigen presentation, primarily the T-cell zones of the secondary lymphoid organs [37, 57, 88, 89]. In order to present the processed antigens to naïve T-cells and to induce a proper immune response, a direct contact between the DC and the T-cell is necessary. To arrange this proximity, a so-called ‘immunological synapse’ if formed between the APC (namely the DC) and the T-cell. This cell–cell contact is mediated by T-cell receptors (TCR), MHC complexes and co-stimulatory molecules, surrounded by a ring of adhesion molecules [21, 25]. The consequence of this ‘handshake’ is the initiation of several signal cascades inside the T-cell and the DCs. The efficiency of these signal transduction events is influenced by three factors: (1) the duration of the cell–cell contact, (2) the number of MHC complexes that induce a signal, and (3) the number of co-stimulatory signals which enhance the information transfer [51, 52, 82]. The provision of co-stimulatory signals by mDCs in the form of cytokines (such as IL-2 or IL-12) and membrane-bound ligands (such as CD80 or CD86) regulate T-cell activation and differentiation [22, 65]. Amongst many other surface molecules that are up-regulated during maturation of DCs, one membrane-bound glycoprotein and member of the IgG superfamily is of outstanding importance, because it represents one of today’s best known surface marker for fully matured human DCs: namely CD83. Already special features of this molecule are found before its cell surface expression, i.e., on the level of gene expression and CD83 messenger RNA (mRNA) processing.

Particular events during CD83 gene expression and mRNA processing

Chromosomal location of CD83 and promoter events

A novel cell-surface molecule expressed by human interdigitating reticulum cells, Langerhans cells, and activated lymphocytes was first described by Zhou et al. [104] and was termed HB-15. Two years later this molecule (in the meantime termed CD83) was characterized as a maturation marker for DCs [106] and in the subsequent years became one of the best known and most typical marker for fully mature DCs that were able to activate naïve T-cells [98, 105–107]. In 1999 the CD83 gene was localized on chromosome 6 band p23 [11] and 1 year later first evidence was provided that the downstream transcription unit for CD83 is triggered by NF-κB and that this signaling pathway plays a crucial role during the induction of an adaptive immune response [59]. Shortly afterwards, Berchtold et al. cloned a 3,037 bp fragment up-stream of the translation initiation codon and—by the help of several deletion mutants—were able to narrow the highest promoter activity down to a 261 bp fragment which contained four SP1 binding sites as well as one NF-κB binding element. Interestingly, TNFα was able to induce the human CD83 promoter, but was strictly dependent on a functional NF-κB element [13]. Evidence for NF-κB regulated expression also came from observations by Dudziak and co-workers. They showed that the viral latent membrane protein 1 (LMP1) of the Epstein–Barr Virus induces CD83 surface expression in B-cells via the NF-κB pathway, thereby confirming previous studies [24].

CD83 mRNA export from nucleus to cytoplasm

In order to achieve proper protein expression, first of all a ‘construction manual’ for the respective protein has to be generated inside the nucleus by transcription. Afterwards, this transcript (yet an unprocessed pre-mRNA) has to undergo several post-transcriptional modifications such as splicing, capping or Poly(A)-tailing [61, 101]. Finally, this matrix has to cross the nuclear membrane, which functions as barrier between the site of transcription (i.e., the nucleus) and the side of translation (i.e., the cytoplasm). The nuclear-cytoplasmic translocation of different forms of RNAs usually proceeds in the form of messenger ribonucleoprotein (RNP) complexes which are transported through supramolecular structures termed the nuclear pore complexes (NPC), which are located all over the nuclear membrane [10, 28, 92]. Several different, but sometimes partially overlapping RNA export pathways exist and manage the nuclear export of different classes of RNA, including tRNAs, rRNAs, U small nuclear RNAs and mRNAs [27, 75, 78].

The majority of cellular mRNAs is exported by the TAP-mediated export pathway. In contrast, the CRM1 mediated export pathway export arranges the nucleocytoplasmic translocation of a small group of RNAs, such as rRNAs or U small nuclear RNAs. This pathway is also subject to viral mechanisms and is for example exploited by the Human Immunodeficiency Virus Type 1 (HIV-1) for the export of its own incompletely spliced or unspliced mRNAs, encoding viral structure proteins and enzymes [14]. As most of the export mediating proteins themselves show low affinity towards RNA, the interaction between transporters and targets is accomplished through adaptor proteins [74, 97].

The eukaryotic initiation factor 5A (eIF-5A) has been reported to be involved in the export of cellular mRNAs from the nucleus to the cytoplasm [14, 26]. eIF-5A binds to the general export receptor CRM1 at the nucleoplasmic part of the NPC and is then translocated into the cytoplasm [79].

For its biological function, eIF-5A undergoes a posttranscriptional processing: two cellular enzymes, the deoxyhypusine-synthase and the deoxyhypusine-hydroxylase catalyze the spermidine dependent mechanism of hypusine modification. It is noteworthy that eIF-5A is the only cellular protein known today which contains the unusual amino acid hypusine (N[ε]-(4-amino-2-hydroxybutyl-lysine)) [66, 67]. The expression level of eIF-5A is very low in iDC but strongly increases during DC maturation. When one of the hypusine modification catalyzing enzymes is blocked by the low molecular weight inhibitor GC7 (N1-guanyl-1,7-diaminoheptane), DCs fail to up-regulate CD83 during DC-maturation. This block of the CD83 mRNA export leads to a reduced T-cell stimulatory capacity [49].

A similar influence on DC activation in vitro and in vivo has been described by Zinser and co-workers. The addition of CNI-1493 (an inhibitor of the deoxyhypusine-synthase) prevented the expression of CD83 during maturation and DC-mediated T-cell stimulation. Furthermore, when applied in an early therapeutic setting it also reduced the clinical symptoms using an experimental autoimmune encephalomyelitis (EAE) model [110].

New insights into the unusual export of the CD83 mRNA came from a recent study by Prechtel and co-workers. They discovered the crucial role of a cellular protein which at a first glance does not seem to be involved in mRNA export at all: HuR. HuR is a member of a family of human RNA-binding proteins that is related to the Drosophila ELAV (embryonic lethal abnormal vision) protein [4, 45]. Until then this protein was described to influence the decay rates of certain mRNAs, representing an important mechanism to control gene expression at the post-transcriptional level [36, 101]. While transcripts that encode housekeeping genes are very stable, so-called early response gene (ERG) mRNAs are very unstable and rapidly degraded. These ERG mRNAs encode proteins such as proto-oncoproteins, cytokines and lymphokines. Their fast decay rate originates from cis-acting instability elements that are usually located inside the 3′ untranslated region (3′UTR) of ERG mRNAs. These instability elements contain regions of adenylate and uridinylate residues and often consist of variable copies of a typical AUUUA pentamer [7, 20]. Therefore, this elements are termed AU-rich elements (AREs) [15, 36, 100]. Various cellular proteins specifically bind to such AREs and can either enhance degradation and thus increase instability, or they act the opposite way and stabilize the labile mRNA. HuR is representative for stabilizing proteins that bind to AREs in the 3′UTR of labile mRNAs [15] and has also been shown to translocate between the nucleus and the cytoplasm in mammalian cells [29]. This shuttling activity of HuR suggested the possibility that this protein binds nascent mRNAs inside the nucleus and protects them from rapid degradation by enhancing their nucleocytoplasmic transport [44].

Although the CD83 mRNA does not contain any sequences that show similarity to a typical ARE, this mRNA is subject to the RNA binding activity of the HuR protein. Surprisingly, this protein–RNA interaction between HuR and the CD83 mRNA does not take place in the 3′UTR, but at a structured element within the CD83 coding sequence. HuR binds with high specificity to this posttranscriptional regulatory element (PRE) and mediates the nuclear export of the CD83 mRNA, having absolutely no influence on the stability of the RNA [68]. Finally, the link between HuR and the CRM1-specific nuclear export pathway has been identified in the form of the cellular protein APRIL (ANP32B) [31]. Taking these data together (summarized in Fig. 1) it becomes obvious that CD83 is indeed an unusual and extraordinary molecule, already at the level of mRNA processing.

Fig. 1 Specific features in the CD83 mRNA export. In strong contrast to the vast majority of cellular mRNAs, the CD83 mRNA is not exported from nucleus to the cytoplasm via the commonly used TAP-pathway, but by the CRM1-mediated nuclear export. 1 The cellular mRNA binding proteins HuR and APRIL shuttle between the nucleus and the cytoplasm. HuR, primarily acting as a mRNA stabilization protein, was shown to protect nascent mRNAs from degradation by actively participating in their export from nucleus to cytoplasm. 2 HuR binds with high specificity to a structured RNA element (termed posttranscriptional regulatory element; PRE), located in the coding sequence. 3 Another cellular protein, APRIL, functions as adaptor molecule, linking the HuR-CD83 mRNA complex to eIF-5A/CRM1 and thus paving the way through the nuclear pore complex (NPC) into the cytoplasm. 4 After the arrival at the location of protein translation, the CD83 surface molecule is generated and transported to the surface. 5 The ‘transporters’ HuR and APRIL are recycled and can re-enter the nucleus for other transport or stabilization activities. NPC: nuclear pore complex, PRE : posttranscriptional regulatory element. For references, please see text.

From mRNA to protein

Species and cell types that express CD83

Homologs of the human CD83 were found in several species: mice, elasmobranch and teleost fish. While the CD83 proteins from the latter ones display ∼28–32% identity to mammalian CD83 [64], mouse CD83 shares 63% amino acid identity with the human form [12, 95], indicating a conserved function in both species and making mice a suitable object to study the function of this molecule. CD83 is the one of the most prominent markers for fully matured DCs. However, DCs are indeed not the only cells that express CD83. Activation of monocytes and macrophages also induces rapid surface expression of CD83. In strong contrast to DCs, surface expression on those cell types is not long lasting and after 8–24 h CD83 has completely disappeared from their surface [18]. Besides mDCs, also some subgroups of T-cells [102], B-cells [48], granulocyte-precursor cells [63], myeolocytes [105], neutrophils [42] and murine thymus epithelial cells [33] express under certain circumstances the CD83 surface molecule. Furthermore, CD83 expression was also detected in Hodgkin cells [87] and Epstein–Barr Virus transformed lymphoblastoid cell lines [24].

The different forms of CD83

Up to date, two different protein isoforms of CD83 have been reported in vivo: a membrane bound form (mCD83) [106] and a soluble form (sCD83) [41]. mCD83 is a highly glycosylated surface protein of the Ig superfamily with a molecular mass of 40–45 kDa [54, 106]. It consists of an extracellular V-type Ig-like domain at the N-terminus, a short intracellular cytoplasmic domain of 39aa length and one transmembrane domain [106]. The soluble form of CD83 is found in healthy donors, but increased levels were detected in a number of patients suffering from hematological malignancies, including patients with chronic lymphatic leukemia (CLL) and mantle cell lymphoma [40] as well as patients affected by rheumatoid arthritis [39]. These data indicate that sCD83 might play an important role in the down-modulation of anti-proliferative immune responses in these patients. Admittedly, the origin of sCD83 is not yet clear. Dudziak and co-workers identified four different transcripts of CD83 in unstimulated Peripheral Blood Mononuclear Cells (PBMCs). Sequence analyses demonstrated that the largest form codes for the transmembrane CD83 (CD83-TM), whereas all of the smaller transcripts (CD83-a, -b and -c) encode for putative soluble forms and are splice variants of full length CD83. However, in iDCs cultured in the presence of GM-CSF and IL-4, the CD83-TM, CD83-a and CD83-b variants were detected on mRNA level. After induction of maturation, CD83-TM was slightly enhanced whereas CD83-b was down-regulated. CD83-a was not changed in its expression and CD83-c was not detected at all [23].

Another hypothesis where sCD83 originates from is that this protein is generated by proteolytic cleavage of the membrane bound CD83-isoform [41]. This theory was supported by the observation that infection of DCs with the Human Cytomegalovirus (HCMV) dramatically reduced T-cell stimulatory capacity of DCs. This is due to a release of sCD83, in this case generated by the cleavage of mCD83 [85] (for further information on CD83 as a viral target to modulate immune responses, please see below).

The different functions of soluble and membrane-bound CD83

Functions of membrane-bound CD83 (extra-thymic functions)

First hints towards the role of the membrane-bound form of CD83 came from studies with viruses. When iDCs were infected with the Herpes simplex virus type 1 (HSV-1) they failed to up-regulate CD83 during maturation [80]. Infection of mDCs resulted in rapid and specific down-modulation of CD83 from cell surface, while other surface markers such as CD80 and CD86 were not influenced at all [50]. Interestingly, in both cases the loss of CD83 led to a strong reduction of the DCs’ T-cell stimulatory capacity, suggesting CD83 acts as an essential enhancer during T-cell activation. Interference with CD83 mRNA export resulted in nuclear trapping of the CD83 mRNA and in consequence led to a loss of CD83 surface expression. This resulted in an equal impact on the T-cell DC interaction, as the DCs failed to satisfactorily activate T-cells [50]. However, all these studies were obtained by the use of agents which might cause some unwanted side effects.

In a publication, Prechtel et al. [70] described a method to efficiently electroporate DCs with small interfering RNA (siRNA). Using this transfection protocol, CD83 expression was inhibited without influencing the surface expression of any other molecule as well as influencing any other specific DC function. The resulting DC population (having a fully mature phenotype, except for the CD83 surface expression) again showed dramatically reduced T-cell activation, underlining and confirming the enhancer function of mCD83 [Prechtel et al., under revision].

In order to obtain further insights into the function of mCD83, Scholler and co-workers performed experiments using a fusion protein of the extracellular domain of CD83 together with an Ig-domain (i.e., CD83-Ig). Co-immobilization of this protein with anti-CD3 mAb simulated the membrane-bound CD83. Surprisingly, CD83-Ig alone was not able to induce strong proliferation of PBMCs, whereas the immobilized protein was definitely able to do so. Furthermore, the ratio of CD8+ to CD4+ T-cells increased by a factor of 2.5. This supported the hypothesis that CD83 has a specific function during the induction of T-lymphocytes [83, 84], which was further confirmed by experiments where the expression of a not jet characterized CD83 ligand (CD83L) was induced both on CD8+ to CD4+ human T-cells by CD28-mediated co-stimulation. Overall, engagement with CD83 provides a signal that specifically supports the expansion of newly primed naive CD8+ T-cells, enhancing the in vitro generation of cytotoxic T-lymphocytes (CTLs) [38]. Additional evidence for the enhancer function of mCD83 was provided by studies, where the poorly immunogenic melanoma cell line K1735 was retro-transfected with CD83 and then implanted subcutaneously into mice. The K1735-CD83 cells formed small tumor nodules that regressed within a week. One month later, half of the mice were challenged with 2 × 106 K1735 wildtype cells, while the other half was challenged with the double amount of K1735 wildtype cells; injection into naïve mice served as a control. Surprisingly, the majority of the CD83-K1735 pre-treated animals showed significantly reduced tumor development or was even tumor free [83]. These observations were fundamentally confirmed by another group that additionally identified CD137 as a co-factor for increased anti-tumor immunity of CD83 [103].

Intra-thymic functions of mCD83

As shown above, the surface associated form of CD83 is of high importance for DCs during the fulfillment of their function as T-cell activators, i.e., during intercellular interactions. First evidence that mCD83 has also an effect on DCs and on other cell types came from studies with CD83 knockout (CD83−/−) mice. When Fujimoto and co-workers compared T-cell populations of wild-type mice with the CD83−/− littermates, they found a severe reduction in peripheral CD4+ single-positive T-cells, while the CD8+ single-positive thymocyte development and numbers were surprisingly normal [32, 33]. Two years later, these data were essentially confirmed by the identification of a mutation within the CD83 gene, which also resulted in a substantially reduced development of CD4+ T-cells. Moreover, the remaining CD4+ T-cells failed to respond normally after allogeneic stimulation, which was due to an altered cytokine expression profile [34]. Fujimoto et al. next crossed their CD83−/− mice with AND mice that carry a MHC class II specific T-cell receptor (TCR; Vα11, Vβ3) and positively select thymocyte from the CD4 lineage [33, 43]. Afterwards, they performed adaptive transfer experiments and transplanted bone marrow cells from CD83−/−AND and AND mice into irradiated CD83−/− and wild-type recipients. In wild-type littermates thymocytes from both AND and CD83−/−AND mice developed normally into CD4+ single-positive cells. In strong contrast, in CD83−/− mice the thymocytes from both donors completely failed to develop into CD4+ single-positive thymocytes. Additionally, the numbers of peripheral CD4+ T-cells were equal in wild-type recipients, whereas the number of peripheral CD4+ T-cells was significantly reduced in the CD83−/− recipients [33]. Although very little is known about the signals and cell surface molecules involved in thymocyte development, a role for DCs as APCs during thymocyte selection and survival has also been discussed [5, 58, 90]. In this respect, Fujimoto and colleagues showed by experiments with the CD83−/− mice that a CD83 signal is required both from thymic endothelial cells on a transitional CD4+/CD8low thymocyte population as well as from DCs during the development of thymocytes (for an overview, please see [32]). This observation is also of particular interest as it has been shown that CD4+/CD25+ T-cells regulate primary and memory T-cell responses against HSV-1 [94]. Thus, viral influence on CD83 surface expression might have severe consequences for the induction of antiviral immune responses (discussed below, please see chapter 5). Figure 2 summarizes the reported effects of mCD83 on T-cells as well on the development of thymocytes.

Fig. 2 Summarized functions of membrane-bound CD83. CTL: cytotoxic T-cells, mCD83: membrane-bound CD83, MLR: mixed leukocyte reaction. For references, please see text.

The functions of soluble CD83 (sCD83)

Characterization of sCD83

The existence of a soluble form of CD83 was first described in 2001. Hock et al. [41] reported that a sCD83 molecule is released from activated DCs as well as from B lymphocytes, and that low levels (121 ± 3.6 pg/ml) of circulating sCD83 are present in sera from normal donors. Interestingly, the sera levels of sCD83 were dramatically increased in patients suffering from hematological malignancies (sCD83 > 1.0 ng/ml) [40] or rheumatoid arthritis (sCD83 > 0.63 ng/ml) [39]. Meanwhile, Lechmann et al. amplified the extracellular domain of the human CD83 (hCD83ext; amino acids 23–128) and expressed it as a GST-fusion protein in bacteria. After biochemical purification and proteolytic removal of the GST-Tag large amounts were available for studying the functions and prospects of this recombinant sCD83 molecule [54]. Several biochemical analyses revealed that hCD83ext (which is often also referred to as sCD83, although the in vivo generation of this molecule is not yet completely clear; see above) adopts a defined three-dimensional structure [54, 55]. Sequence alignment of CD83 between different species revealed the presence of five cysteines in the extracellular Ig-domain of the protein and opened up the possibility that four of the five cysteines are involved in the formation of intramolecular disulfide bonds. The fifth cysteine seemed to be essential for the function of an intermolecular covalent disulfide bond, thus leading to the dimerization of the extracellular protein domains. And indeed, when the fifth cysteine at position 129 was mutated into a serine, dimerization no longer took place. However, the mutated protein was able to inhibit DC-mediated allogeneic T-cell stimulation in a Mixed Leukocyte Reaction (MLR) as efficiently as the wild-type hCD83ext [53, 55]. Furthermore, both sCD83 isoforms showed similar inhibitory effects on EAE in vivo and also a comparable biological half-life of approximately 2–3 h 108].

Effects of sCD83 on DCs

The question, whether sCD83 influences DCs in a kind of feedback mechanism was first investigated when iDCs were matured with a standard cytokine cocktail [93] in the presence or absence of sCD83 (i.e., hCD83ext). When 4 μg/ml hCD83ext were added at day 7–8, first a considerably reduced surface expression of mCD83 was detected (from 96% in mock-treated to 65% in hCD83ext treated DCs). Interestingly, the surface expression of co-stimulatory molecules such as CD80 and CD86 was not influenced and a low number of CD14+ cells (CD14 represents a marker for immature cells) indicated appropriate maturation. When sCD83 was added at day 5–8 during the maturation period, the number of CD14+ cells strongly increased (from 7 to 59%), indicating an incompletely matured population. Furthermore, CD83 surface expression was reduced much more efficiently, this time accompanied by reduced CD80 surface expression. Thus, sCD83 was able to interfere with DC maturation [55].

Another effect of sCD83 on DCs is the influence on the cellular cytoskeleton. As DCs posses the ability to migrate to secondary lymphoid organs, where close encounters with naïve T-cells are established, a functional cytoskeleton is of utmost importance [2, 96]. After incubation with high doses of sCD83 (10 μg/ml), mDCs rounded off, developed only short, truncated or even no veils and were completely inhibited in their skill to form clusters with T-cells [47].

Effects of sCD83 on T-cells

The recombinant soluble form of human CD83 inhibits DC-mediated T-cell stimulation in vitro in a concentration-dependent manner [55, 84]. Moreover, in vivo sCD83 was demonstrated to have striking effects on T-cells. Therefore, the murine EAE model was used. EAE is a CD4+ T-cell mediated disease model for the early inflammatory stage of human multiple sclerosis, resulting in CD45+ leukocyte infiltrations in the brain during the acute phase of the disease [35]. It was reported that as few as three injections of sCD83 almost completely prevented the clinical symptoms associated with EAE in different therapeutic setting, such as tail weakness, paraparesis and paraplegia. Even when some of the symptoms of EAE have already developed during the course of the disease, injections of sCD83 could clearly reduce the paralytic symptoms. Also leukocyte infiltrations of CD45+ cells into the brain and into the spinal cord (typical for progressive EAE) were almost completely abolished [109].

Implanting immunogenic P815 tumor cells directly into recipient mice usually results in tumor growth. When a form of sCD83 was injected right afterwards, the tumor cell implantation resulted in tumors that were twice as large as in mock-injected mice. This enhances the hypothesis that sCD83 down-modulates anti tumor immune responses by directly influencing T-cell (sub)populations, particularly the development of cytotoxic T-cells [84].

In a recent sutdy, Xu and co-workers generated a form of mouse soluble CD83 (CD83-Ig) by linking the extracellular domain of murine CD83 with human IgG1alpha Fc tail. This mouse sCD83 was then purified from transfected COS-7 cell. They could demonstrate that the treatment of recipient mice with CD83-Ig significantly delayed allograft rejection in a fully major histocompatibility complex-mismatched murine skin transplantation model. Especially, when T cells originated from recipients treated with CD83-Ig were re-stimulated with donor-specific splenocytes, they showed a significant reduced responding capability as compared with that of originated from control recipients [111].


The reported effects of sCD83 on DCs as well T-cells are summarized in Fig. 3.

Fig. 3 Summary of the functions of soluble CD83. sCD83: soluble CD83, EAE: experimental autoimmune encephalomyelits. For references, please see text.

CD83 as a target for viral immune escape mechanisms

DCs are essential for mounting an antiviral immune response. Thus, influencing the DCs’ biology represents an efficient way to avoid activation of the immune system and thereby overriding the host’s defence mechanisms. Several viral pathways have been described how viruses manipulate DCs for their own interests [9, 46, 77]: HIV-1 for example is able to infect iDCs and inhibits maturation via its viral product Vpr [62]. Furthermore, HIV-1 subverts DCs’ function leading to the spread of the virus. At an early phase of transmission, DCs capture HIV-1 particles at mucosal surfaces. Afterwards, HIV-1 induces migration of the DCs [99] and in consequence they transmit the virus to T-cells in secondary lymphoid tissues [56]. Also members of the Herpesviridae family are able to interfere with DCs’ biology. HSV-1 for example is able to block maturation of infected iDCs [80] as well as to prevent infected mDCs from migration [69]. In this respect, a very interesting observation was that the CD83 surface molecule is a target for several viruses. HCMV, for example, is able to infect both iDCs and mDCs and consequently inhibits the stimulation of T-cell proliferation [6, 71, 85]. Surprisingly, as a consequence of the HCMV infection, a soluble form of CD83 is shed from the cell surface by proteolytic cleavage and subsequently blocks T-cell stimulation, exactly the same way as described for the recombinantly expressed hCD83ext (please see above) [85].

However, when mDCs were infected with HSV-1, a strong downregulation of the cell surface expression of CD83 was observed. In strong contrast to the HCMV infection, this is not due a shedding of the CD83 from surface, but to a very fast and efficient degradation of the CD83 molecule inside the infected DC. It is noteworthy, that already 10 h p.i. CD83 was almost completely removed from the cell surface, whereas other co-stimulatory molecules such as CD80 and CD86 were not influenced in any way and were still expressed at high levels on the cell surface. Nevertheless, the CD83 down-modulation correlated with a reduced T-cell stimulatory capacity [50].

Figure 4 summarizes different effects of the HSV-1/HCMV infection on membrane bound CD83 on mDCs.

Fig. 4 Viruses specifically target CD83 to evade immune responses. Herpes simplex virus type 1 (HSV-1) as well as Human Cytomegalovirus (HCMV) target CD83 to influence T-cell stimulation by mDCs, but use completely different mechanisms. 1 The infection of mDCs with HSV-1 results in a rapid intracellular degradation of surface associated CD83, whereas other co-stimulatory molecules such as CD80 and CD86 are not influenced. 2 This results in ‘mDCs’, with low levels of membrane-bound CD83 (CD83− mDCs). 3 In strong contrast, the infection of mDCs with HCMV does not lead to degradation, but to a proteolytic cleavage of the surface CD83. 4 Thus, a form of soluble CD83 is generated that influences the T-cell stimulatory activity of mDCs. 5 Both cases—shedding of sCD83 as well as degradation of mCD83—result in strongly reduced T-cell activation, leading to strongly reduced immune responses. mCD83 membrane-bound CD83, sCD83: soluble CD83, HSV-1: Herpes simplex virus type 1, HCMV: Human Cytomegalovirus. For references, please see text.

To summarize, recent investigations have provided new insights on functions and prospects for the CD83 molecule. Regarding autoimmune diseases, infectious diseases, T-cell based allergic reactions, host-versus-graft/transplant rejection and immune therapy for malignant tumors, CD83 might play a key role in the establishment of therapeutic applications. Hopefully more and more insights on CD83’s mode of action and impact during immune functions will be discovered over the next years and provide the basis for new therapeutic strategies.

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