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Alternative Splicing Generates Putative Soluble CD83 Proteins That Inhibit T Cell Proliferation¹

Diana Dudziak^2,*, Falk Nimmerjahn^3,, Georg W. Bornkamm^* and Gerhard Laux^*

^* Institute of Clinical Molecular Biology and Tumor Genetics, GSF National Research Center (GSF) for Environment and Health and Clinical Cooperation Group of Pediatric Oncology, GSF and Children’s Hospital of the Technical University, Munich, Germany

	Abstract

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CD83 is expressed on mature dendritic cells and activated lymphocytes and has been implicated to play an important role during T cell development in the thymus. In contrast, not much is known about the function of CD83 in the periphery. Soluble forms of CD83 have been detected in the serum, but neither the function nor the mechanism of how these soluble forms of CD83 are generated are fully understood. In this study, we report the identification of four different transcripts of CD83 in unstimulated PBMCs. Sequence analysis demonstrated that the longest form codes for transmembrane CD83 (CD83-TM), whereas the smaller transcripts are splice variants of full-length CD83, coding for putative soluble CD83 proteins. Stimulation of PBMCs with PHA, TNF-, or LPS leads to the up-regulation of the full-length CD83 transcript and to a strong down-regulation of two of the three smaller transcripts. The smallest CD83 splice product can be translated efficiently into protein, and recombinant soluble CD83 shows a strong inhibitory effect on T cell proliferation in MLRs. Our results suggest that the constitutive production of soluble forms of CD83 under steady-state conditions may have an important function in regulating immune homeostasis.

	Introduction

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The surface glycoprotein CD83 has a molecular mass of 40–45 kDa and belongs to the Ig superfamily (1, 2). It consists of an extracellular V-type Ig-like domain at the N terminus, one transmembrane (TM)⁴ domain, and a short intracellular cytoplasmic domain of 39 aa (2). CD83 is described as a cell surface marker of mature dendritic cells including Langerhans cells in the skin and interdigitating reticulum cells in the T cell zones of the lymph nodes (2, 3, 4, 5). In immature monocyte-derived dendritic cells (MoDCs), CD83 is up-regulated after stimulation with LPS, TNF-, or CD40L (6, 7, 8). Addition of high doses of IL-4, GM-CSF, and TNF- induces the expression of CD83 on monocytes, granulocyte-precursor cells, and myelocytes (9, 10). It was also shown that CD83 is expressed on polymorphonuclear neutrophils (11) and on murine thymus epithelial cells (12). Furthermore, CD83 is expressed on Hodgkin cells (13) and EBV-transformed lymphoblastoid cell lines (2, 14).

The function of CD83 remains largely unknown. CD83 knockout mice showed a block in the development of CD4⁺ single-positive T cells (12). CD83 expression on mature dendritic cells and activated lymphocytes (1, 2, 10, 15) suggests that CD83 might be involved in activating immune effector cells. Along these lines, melanoma cells that were engineered to express cell surface CD83 are rejected after injection into C3H/HeN mice, whereas wild-type melanoma cells showed tumor growth (16, 17).

The addition of a human CD83-Ig fusion protein or a human soluble CD83 protein lacking the TM and cytosolic domain strongly inhibited MLR or DC-mediated allogeneic T cell proliferation, demonstrating that soluble CD83 could have an inhibitory function (18). Moreover, soluble CD83 was able to prevent experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice (19). Latest studies suggest that soluble CD83 is present in the serum of healthy donors (20, 21, 22) and it was proposed that the mechanism for the generation of soluble CD83 is shedding of cell surface-associated CD83. However, soluble forms of cell surface proteins can also result from alternative splicing as reported for several members of the Ig superfamily, e.g., CD80 (B7-1), CD86 (B7-2), CTLA-4, or CD28 (23, 24, 25, 26, 27, 28).

In this study, we report that alternative splicing generates soluble forms of CD83. Stimulation of freshly isolated PBMCs with PHA, LPS, or TNF-/IL-1 up-regulates transcripts encoding TM CD83 and down-regulates transcripts coding for alternatively spliced products of CD83. These putative soluble forms of CD83 proteins are characterized by a partial deletion of the extracellular and the TM domain. Soluble CD83 displayed inhibitory effects in MLRs and, therefore, might have important immunoregulatory functions in vivo.

	Materials and Methods

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Isolation of human PBMCs and DCs

Human PBMCs were isolated by centrifugation on Ficoll-Paque (Amersham Biosciences). Isolated PBMCs were cultured in complete medium (RPMI 1640 medium; Invitrogen Life Technologies) supplemented with 10% FCS (Dynacyte), 100 U/ml penicillin, 100 µg/ml streptomycin, 1 mM sodium-pyruvate, 2 mM L-glutamine (all from Invitrogen Life Technologies) and were left either unstimulated or stimulated with PHA (1 µg/ml), LPS (1 µg/ml), or a mix of TNF- (2.5 ng/ml; Sigma-Aldrich), IL-1 (1 ng/ml; Sigma-Aldrich), and PGE₂ (1 ng/ml; Sigma-Aldrich) for the indicated time. Human DCs were generated as described (4) and matured with LPS (100 ng/ml) or TNF-/IL-1/PGE₂.

Cloning and sequencing of the CD83 mRNA splice products

Total RNA of PBMCs was extracted using the RNeasy Midi kit (Qiagen). RNA from human tissues was kindly provided by J. Mautner (Clinical Cooperation Group of Pediatric Oncology, GSF, Munich, Germany). Single-stranded cDNA was synthesized from 5 µg of total RNA by reverse transcription using Superscript reverse transcriptase (Invitrogen Life Technologies) and an oligo-dT primer (Amersham Biosciences) at 42°C. CD83 cDNA was amplified with primers designed to amplify the entire coding sequence of CD83 (5'-GCGGGGGAATTCCTCGAGATGTCGCGCGGCCTCCAGCTTC-3' and 5'-CCCCGGGCGGCCGCTCATACCAGTTCTGTCTTGTGAGGAGTC-3'; Metabion). The PCR was performed using PFU DNA Polymerase (Promega) as follows: 94°C for 4 min, than 35 cycles of 94°C for 1 min, 57°C for 1 min, and 72°C for 2 min, followed by a final extension step at 72°C for 10 min (PerkinElmer). The amplified fragments were separated on a 2% agarose gel and visualized by ethidium bromide. After excision from the gel, resulting products were cloned into the pcDNA3.1 vector. Cloned cDNAs were verified by sequencing (Sequiserve). RNA integrity and cDNA synthesis was proven by amplifying GAPDH cDNA (5'-ACCACAGTCCATGCCATCAC-3' and 5'-TCCACCACCCTGTTGCTGTA-3').

Generation of His-tagged soluble CD83

CD83 splice variants were tagged with a C-terminal histidine hexapeptide. The cDNAs CD83-TM, CD83-a, CD83-b, and CD83-c were reamplified using PFU DNA polymerase (Promega) with the 5' primer (5'-GCGGGGGAATTCCTCGAGATGTCGCGCGGCCTCCAGCTTC-3') and 3' primers inserted the histidine tag upstream of the resulting stop codon (5'-CCCCGGGCGGCCGCTCAGTGATGGTGATGGTGATGTACCAGTTCTGTCTTGTGAG-3' and 5'-CCCCGGGCGGCCGCTTAATGGTGATGGTGATGAGTAGAAAATAACCAGAGCCAG-3'). The PCR products were cloned into the EcoRI/NotI sites of the pcDNA 3.1 vector and verified by sequencing.

293-T cells were cultured in DMEM medium supplemented with 10% FCS (Dynacyte), 100 U/ml penicillin, 100 µg/ml streptomycin, 1 mM sodium-pyruvate, 2 mM L-glutamine (all from Invitrogen Life Technologies). His-tagged variants and membrane CD83-His were transiently transfected into 293-T cells by calcium phosphate method (29). After transfection, 293-T cells were grown for 7 days in serum-free medium (SFMII 293; Invitrogen Life Technologies). After harvesting the medium, the soluble CD83 variants were enriched by Ni-NTA beads, purified under native conditions (Qiagen) and analyzed by Western blot. When used in MLR, CD83-c-His protein was dialyzed at 4°C overnight against PBS and further purified and enriched by gel filtration (Ultrafree-4 filter; Amicon).

Western blot analysis

Purified protein (0.5 µg) or 15 µl of supernatant was electrophoretically separated on a 15% SDS polyacrylamide gel under reducing conditions and transferred onto a polyvinylidene difluoride membrane (Hybond P; Amersham Biosciences). Blocking was done for 1 h in TBST buffer (10 mM Tris-HCl, pH 7.5, 100 mM NaCl, 1% Tween 20) containing 5% milk (Merck). Membranes were incubated with either anti-CD83 Ab (1:500 to 1:1000, HB15A; Immunotech) or anti-His Ab (1:500; Roche) in TBST containing 3% dry milk overnight at 4°C. After washing, membranes were incubated with peroxidase-labeled goat anti-mouse IgG Ab (1:2000 to 1:5000; Dianova) for 1 h at room temperature. Finally, blots were washed three times. Proteins were visualized using the ECL system (Amersham Biosciences).

FACS analysis

To evaluate cell surface expression of PBMCs, cells were washed in FACS buffer (PBS/0.5% BSA/0.02% sodium azide) and incubated with PE-conjugated mouse anti-human CD83 (HB15A; Coulter Immunotech) or isotype control IgG2b Abs (BD Biosciences) for 30 min on ice. Flow cytometry was performed on a FACSCalibur cytometer (BD Biosciences) and analyzed with CellQuest acquisition software.

Allogeneic MLR

Allogeneic PBMC stimulation was measured in a standard MLR. Stimulatory cells were inactivated by gamma-irradiation (20 Gy), cells were washed three times with complete RPMI 1640 medium. Stimulatory cells (1 x 10⁵/well) were incubated with allogeneic PBMC in 96-well microtiter plates in complete medium at a ratio of 1:1 and 1:10 for 5 days. Purified recombinant CD83-c-His protein (0.75, 1.5 µg/ml) was added immediately. As control, His-tagged neomycin phosphotransferase (NeoR-His, 1.5 µg/ml, kindly provided by J. Mautner) or PBS was used. For the determination of cell proliferation the cells were pulsed with [³H]thymidine (1µCi/well; Amersham Biosciences) for the last 16 h. Incorporation of [³H]thymidine into DNA was counted with TopCount NXT counter (Packard Instrument). Data are expressed as mean and SD.

	Results

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Identification of alternatively spliced variants of the CD83 mRNA

Recently, it was shown that soluble CD83 variants are present in the serum of healthy individuals and that they are enriched in leukemia patients (20, 21, 22). To examine whether soluble CD83 forms are generated by alternative splicing, we isolated total RNA from PBMCs that were either left untreated or treated for 4 or 16 h with PHA (Fig. 1A) or for 16 h with LPS or TNF-/IL-1, respectively (Fig. 1B). Stimulation of PBMCs with PHA was followed by FACS analysis with an anti-human CD83-PE-labeled Ab showing a strong induction of CD83 on the cell surface of PBMCs 4 h after PHA addition (Fig. 1C). The amplification of the CD83 coding sequence by RT-PCR using primers flanking the ATG initiation codon and the translation termination codon revealed the constitutive expression of four transcripts by nonactivated PBMCs, with sizes of 618, 599, 389, and 282 bp (Fig. 1A, lanes 1, 4, and 7). Subsequent cloning (Fig. 2, A and B) and sequencing of these fragments identified the largest band as full-length CD83 (CD83-TM), whereas the smaller fragments were truncated versions of CD83 (Fig. 2, A and B). The 599-bp fragment (CD83-a) lacks bp 364–383; the 389-bp fragment (CD83-b) has a deletion between bp 154 and 383; and the smallest fragment (CD83-c) misses bp 154–489. According to the genomic organization of the human CD83 gene on chromosome 6 (AL022396 and AL133250) the smaller RNAs are generated by alternative splicing of either the last 19 bp of exon 3 (CD83-a), skipping of the complete exon 3 (CD83-b) or exon 3 and 4 (CD83-c). Exon 3 is coding for the largest part of the V-type Ig-like domain, and exon 4 is coding for the TM domain of CD83. Additionally, we could define the following intron sizes of intron 1 with 101 bp, intron 2 with 13,454 bp, intron 3 with 1,900 bp, and intron 4 with 1,352 bp. Because of deletions in the CD83-a and CD83-b splice products the reading frame changes, generating a novel short amino acid sequence with an as yet unknown function. Finally, the frame shift results in a stop codon (TAA) at nucleotide position 450 after the translation initiation codon of the full-length open reading frame (ORF) of CD83. In the CD83-c splice product, the ORF of the cytoplasmic domain is not changed in comparison to full-length CD83 mRNA (Fig. 2, A and B). These data suggest that alternative CD83 transcripts lacking the TM domain result in putative soluble CD83 variants.

View larger version (42K): [in this window] [in a new window]   FIGURE 1. Identification of alternatively spliced CD83 mRNA variants. PBMCs from three healthy volunteers (I–III) were isolated and left either untreated (A, lanes 1, 4, and 7; B, lanes 1 and 4; C, upper part) or were stimulated for 4 (A, lanes 2, 5, and 8; C, lower part) or 16 h (A, lanes 3, 6, and 9; B, lanes 2 and 4) with PHA (A) or LPS or TNF-/IL-1 (B). A total of 1 x 107 cells were harvested and total RNA was isolated (A and B); and additionally, 1 x 105 cells were used for FACS analysis (C). A and B, Total RNA was transcribed into cDNA, and RT-PCR using primers spanning the whole ORF was performed. GAPDH was used as a control. C, A total of 1 x 105 cells were incubated with human CD83-PE-labeled Ab (y-axis) and analyzed by flow cytometry. The result represents one of four independent experiments.

View larger version (24K): [in this window] [in a new window]   FIGURE 2. CD83 splice forms and sequences. A, Model of the exon-intron structure of human CD83. The gray boxes represent coding parts of the CD83 exons and the numbers refer to the base pairs of full-length membrane CD83. Exon 1 is coding for a signaling peptide, exon 2 and exon 3 are coding for the extracellular domain of CD83, exon 4 contains the TM region, and exon 5 contains the intracellular domain of CD83. A and B, In CD83-a, a part of exon 3 is excluded (19 bp); in the splice variant CD83-b, exon 3 is completely spliced out; and in the splice product CD83-c, exon 3 and exon 4 are missing. B, Sequence analysis of the CD83 splice variants. The splicing in CD83-a and CD83-b leads to a change in the reading frame, resulting in a new stop codon at nucleotide position 450. In CD83-c, the ORF is preserved.

Tissue distribution of CD83 splice variants

To determine the distribution of the CD83 transcripts in human tissue, we performed RT-PCR using primers spanning the whole ORF. The TM form as well as the splice forms were detected in tonsils, bone marrow, and testis. TM-associated CD83 was detectable in spleen, thymus, brain, kidney, adrenal gland, lung, ovary, and uterus, and only a little expression was found in skin, small intestine, and liver. There was no expression of CD83 variants in heart, pancreas, and skeletal muscle. GAPDH was amplified as a control (Fig. 3, A and B).

View larger version (57K): [in this window] [in a new window]   FIGURE 3. Tissue distribution of CD83 splice variants. CD83 splice products are selectively expressed in unstimulated blood PBMC, bone marrow (BM), tonsil, and testis. Using primers for the full-length ORF, the expression of CD83 splice variants was analyzed by RT-PCR in different human tissues (A and B) or isolated immature MoDCs (0 h) and for 8 and 24 h with LPS or TNF-/IL-1 matured DCs (C). The amplified fragments were visualized by ethidium bromide staining. As control, PCR with GAPDH primers was done.

Expression of recombinant soluble CD83

To study the function of the splice products, all cloned splice variants were fused to a hexahistidine-tag at the very C terminus. 293-T cells were transfected with the splice products, and Western blot analysis of the supernatants and Ni-NTA-enriched proteins was performed. Only the in-frame CD83-c splice product missing exon 3 and 4 could be detected as protein in the supernatant of transfected 293-T cells (Fig. 4A). No protein expression was observed for the splice products CD83-a and CD83-b in the supernatant or in total cell extracts of transfected 293-T cells (data not shown). CD83 cell surface expression could only be detected by transfection of 293-T cells with full-length CD83. None of the CD83 splice products was expressed on the cell surface (data not shown). These results indicate that CD83-c is the only splice product expressed as a functional protein and is secreted into the supernatant.

View larger version (22K): [in this window] [in a new window]   FIGURE 4. Inhibitory effect of recombinant soluble CD83-c in MLRs. A, Purified His-tagged CD83-c protein was analyzed on an SDS-PAGE gel and visualized by Western Blot either with an anti-human-CD83 (HB15A) or an anti-6xHis Ab. B, Allogeneic MLR was performed using freshly isolated human PBMCs from healthy volunteers as described in Materials and Methods. Responder cells were cultured with irradiated allogeneic stimulator cells as indicated. Highly purified recombinant CD83-c-His protein (0.75, 1.5 µg/ml) or an irrelevant control protein was added immediately. Results are expressed as mean cpm ± SD. One representative of four independent experiments with different human blood donors is shown.

To further investigate the functionality of the CD83-c splice product, we tested the purified CD83-c-His protein in allogeneic MLRs. The CD83-c-His protein was harvested and purified from serum-free supernatants from transiently transfected 293-T cells. As controls, His-tagged NeoR protein or PBS were used. The proliferation of the cells was measured by [³H]thymidine incorporation. The addition of increasing amounts of CD83-c-His had an inhibitory effect on the proliferation of T cells in these MLRs, leading to a complete inhibition of proliferation at the highest CD83-c-His concentration (1.5 µg/ml). At the same time, untreated cells or cells treated with an irrelevant protein showed no such block in proliferation (Fig. 4B). These data suggest an inhibitory function of soluble CD83 in the immune system.

	Discussion

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Soluble forms of cell surface molecules can be generated either by splicing as in the case of IL-4R (30), IL-7R (31), or Fas (32); enzymatic cleavage of the extracellular domain as in the case of TNF (33) and IL-2R (34); or both as was shown before for IL-6R (35). For different costimulatory molecules like CD28, CTLA-4, or CD86, alternative splicing was described (23, 24, 25, 26, 27, 28). These soluble counterparts of TM proteins have been described to have important functions, e.g., to potentiate proliferation and lymphokine production by human T cells stimulated with an anti-CD3 Ab (24). The existence of biological active soluble CD83 has been described recently (20, 21, 22) and it was suggested that soluble CD83 is produced by enzymatic cleavage of the cognate membrane form (20).

In this study, we have identified three alternative spliced transcripts of CD83, named CD83-a, CD83-b, and CD83-c, which are constitutively expressed by nonactivated human PBMC in addition to the full-length transcript encoding the membrane-bound form of CD83.

The human CD83 gene is a single copy gene organized in five exons (2) similar to the mouse CD83 gene (12), and the TM domain is encoded by exon 4. In all three alternatively spliced CD83 mRNAs, the part encoding the TM domain is deleted either by partial (CD83-a) or complete deletion of exon 3 (CD83-b) or exon 3 and 4 (CD83-c). Whereas CD83-b and CD83-c mRNAs use common splice donor and splice acceptor sites CD83-a shows an unconventional splice donor site within exon 3, which was also described for alternatively spliced CD28 mRNA (25). Besides the TM domain, in all three splice products, parts of the extracellular V-type Ig-like domain are lost, and furthermore, in CD83-a and CD83-b, the coding sequence of the TM domain is changed to an amino acid sequence with unknown function and no similarities to other known proteins. Although all three forms are highly expressed on RNA level, only CD83-c is translated into a detectable protein after transfection into 293-T cells. At present it cannot be excluded that these other versions of CD83 are expressed as functional proteins as well and that 293-T cells lack cofactors that might be necessary for stabilization of CD83-a and CD83-b.

Our data suggest that soluble CD83 expressed under noninflammatory conditions has a negative immunomodulatory function preventing unspecific effector cell activation. Soluble CD83 has been identified in the sera of healthy individuals, supporting a role of this protein variant under steady-state conditions. Interestingly, the amount of soluble CD83 was elevated in the sera of several leukemia patients (21), which might lead to an increased threshold for T cell activation in these patients. After induction of inflammatory cytokines by polyclonal activators such as PHA, these inhibitory CD83-splice products are down-regulated, which might relieve this inhibitory effect. The most potent cells for induction of an immune response are dendritic cells (36). After induction of dendritic cell maturation these cells strongly up-regulate CD83. Therefore, the expression of soluble CD83-c in immature DCs might be a potential mechanism to suppress immune cell activation under steady-state conditions. However, we were not able to detect the alternatively spliced mRNAs in human myelocytic dendritic cells cultured in the presence of GM-CSF and IL-4. Whereas no CD83 protein could be detected on the cell surface (data not shown), at the RNA level, these cells exclusively expressed the CD83 mRNA encoding for the TM form. This conforms with the notion that IL-4/GM-CSF-treated dendritic cells have been referred to as intermediate rather than immature DCs (37), suggesting that these cells are no longer in an immature state. Hock et al. (20) have found enhanced levels of soluble CD83 in the supernatant of TNF- or LPS matured dendritic cells using a rabbit polyclonal Ab. This finding might be explained by a delayed release of the soluble CD83 protein by dendritic cells. Indeed we have shown that CD83 protein can be found in intracellular vesicles before it is expressed at the cell surface (14). Alternatively, it is possible that under these in vitro culture conditions CD83 is shed from the plasma membrane of dendritic cells. However, it is not clear if soluble CD83 protein generated under these conditions is functional and can suppress T cell proliferation. We are currently addressing the role of soluble CD83 in dendritic cells in greater detail.

Combined with previous studies that identified soluble CD83 in human serum, our studies suggest that the generation of soluble CD83 by alternative splicing is tightly regulated and might be an important mechanism for immune cell activation.

	Acknowledgments

 
We acknowledge the advice and human RNAs provided by J. Mautner. We thank A. Steinkasserer and J. Hauber for helpful discussions. For technical assistance, we are grateful to G. Marschall.

	Disclosures

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The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from Deutsche Forschungsgemeinschaft (SFB455; to F.N.). G.W.B. was supported by Fonds der Chemischen Industrie.

² Address correspondence and reprint requests to Dr. Diana Dudziak at the current address: Laboratory of Molecular Immunology, The Rockefeller University, Box 220, 1230 York Avenue, New York, NY 10021. E-mail address: dudziad{at}rockefeller.edu

³ Current address: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021

⁴ Abbreviations used in this paper: TM, transmembrane; MoDC, monocyte-derived dendritic cell; ORF, open reading frame.

Received for publication September 15, 2004. Accepted for publication March 15, 2005.

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