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J Biol Chem, Vol. 273, Issue 41, 26281-26284, October 9, 1998

COMMUNICATION
T Cell Receptor zeta  Allows Stable Expression of Receptors Containing the CD3gamma Leucine-based Receptor-sorting Motif*

Jes DietrichDagger and Carsten Geisler§

From the Institute of Medical Microbiology and Immunology, University of Copenhagen, The Panum Institute, DK-2200 Copenhagen, Denmark

    ABSTRACT
Top
Abstract
Introduction
Procedures
Results & Discussion
References

The leucine-based motif in the T cell receptor (TCR) subunit CD3gamma constitutes a strong internalization signal. In fully assembled TCR this motif is inactive unless phosphorylated. In contrast, the motif is constitutively active in CD4/CD3gamma and Tac/CD3gamma chimeras independently of phosphorylation and leads to rapid internalization and sorting of these chimeras to lysosomal degradation. Because the TCRzeta chain rescues incomplete TCR complexes from lysosomal degradation and allows stable surface expression of fully assembled TCR, we addressed the question whether TCRzeta has the potential to mask the CD3gamma leucine-based motif. By studying CD4/CD3gamma and CD16/CD3gamma chimeras, we found that CD16/CD3gamma chimeras associated with TCRzeta . The CD16/CD3gamma -TCRzeta complexes were stably expressed at the cell surface and had a low spontaneous internalization rate, indicating that the leucine-based motif in these complexes was inactive. In contrast, the CD4/CD3gamma chimeras did not associate with TCRzeta , and the leucine-based motif in these chimeras was constitutively active resulting in a high spontaneous internalization rate and low expression of the chimeras at the cell surface. Thus, our data demonstrate that TCRzeta allows stable cell surface expression of receptors containing CD3gamma leucine-based motifs by its potential to mask such motifs.

    INTRODUCTION
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Abstract
Introduction
Procedures
Results & Discussion
References

The T cell receptor (TCR)1 is a multimeric receptor composed of the ligand binding Tialpha beta dimer and the signal transducing subunits CD3gamma epsilon and CD3delta epsilon and the TCRzeta zeta dimer (1, 2). Only completely assembled octameric Tialpha beta CD3gamma epsilon delta epsilon zeta zeta complexes are efficiently expressed at the cell surface of mature T cells to ensure proper TCR functions. Thus, very selective mechanisms that only allow expression of completely assembled and functional TCR must exist in T cells. Several studies have indicated that the TCRzeta chain plays important roles in such mechanisms. Thus, the TCR is not or is only very weakly expressed at the cell surface of T cells from TCRzeta knock-out mice and in the TCRzeta -deficient T cell variant MA 5.8 (3-6). In the MA 5.8 variant, hexameric Tialpha beta CD3gamma epsilon delta epsilon complexes are assembled in the endoplasmic reticulum in the absence of TCRzeta and subsequently transported via the Golgi apparatus to the lysosomes for degradation (6). Furthermore, association of TCRzeta to the rest of the TCR seems to be critically dependent on the assembly of hexameric Tialpha beta CD3gamma epsilon delta epsilon complexes, and TCRzeta does not associate with partial TCR complexes in T cell variants lacking Tialpha , beta , or CD3gamma (7-10). Thus, the selective expression of only completely assembled TCR at the T cell surface seems to be ensured by the TCRzeta chain (11, 12). However, it still remains to be explained how the TCRzeta chain redirects the sorting of incomplete TCR from a degradative pathway to the cell surface.

The observation that incompletely assembled TCR complexes are sorted to a degradative compartment and not expressed at the cell surface suggests that receptor-sorting motifs with the capacity to sort receptors to the lysosomes must be active in incomplete TCR (6). We and others have recently described a leucine-based (L-based) receptor-sorting motif (S126DKQTLL132) in the cytoplasmic tail of CD3gamma (13-15). When active, the L-based motif is recognized and bound by clathrin-coated vesicle adaptor proteins either at the trans-Golgi network or at the plasma membrane (15-17). This leads to sorting of receptors to the lysosomes and to rapid receptor internalization, respectively. In completely assembled TCR, the CD3gamma L-based motif is inactive and not accessible for adaptor proteins unless phosphorylated (14). In contrast, in chimeric Tac/CD3gamma and CD4/CD3gamma molecules, the motif is constitutively active independently of phosphorylation, and like hexameric Tialpha beta CD3gamma epsilon delta epsilon complexes, these chimeras are rapidly transported to the lysosomes for degradation (6, 13, 15). From these observations it may be suggested that the CD3gamma L-based motif is active in incompletely assembled TCR and that TCRzeta allows cell surface expression of completely assembled Tialpha beta CD3gamma epsilon delta epsilon zeta zeta complexes by masking this motif. In this study, we addressed the question whether TCRzeta has the potential to mask the CD3gamma leucine-based motif.

By analyzing receptor expression and sorting of mutated TCR and chimeric CD4/CD3gamma and CD16/CD3gamma molecules, we found that similar to the TCR, the CD16/CD3gamma chimera was stably expressed at the cell surface in association with TCRzeta . Furthermore, both the TCR and the CD16/CD3gamma -TCRzeta complexes had low spontaneous internalization rates indicating that the CD3gamma L-based motif in these multimeric complexes was inactive. As is true for the TCR, the CD3gamma L-based motif in the CD16/CD3gamma -TCRzeta complexes was activated following protein kinase C (PKC) activation, which resulted in a rapid internalization of the complexes from the cell surface. In contrast, the CD4/CD3gamma chimera did not associate with the TCRzeta chain and the CD3gamma L-based motif in these chimeras was constitutively active resulting in a high spontaneous internalization rate and low cell surface expression of the chimera. Thus, our data demonstrate that the TCRzeta chain allows stable cell surface expression of receptors containing a CD3gamma L-based motif most probably by masking this motif.

    EXPERIMENTAL PROCEDURES
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Abstract
Introduction
Procedures
Results & Discussion
References

Cells and Reagents-- JGN, a TCR cell surface negative variant of the human T cell line Jurkat that synthesizes no CD3gamma , was produced in our own laboratory (10). Cells were cultured in RPMI 1640 medium supplemented with penicillin 2 × 105 units/liter (Leo Pharmaceutical Products, Ballerup, Denmark), streptomycin 50 mg/liter (Merck, Darmstadt, Germany), and 10% (v/v) FCS (Life Technologies, Paisley, UK) at 37 °C in 5% CO2. Phycoerythrin (PE)-conjugated and purified mouse anti-human CD3epsilon (UCHT1), rat anti-mouse CD4 (L3T4), and mouse anti-human CD16 (3G8) monoclonal antibodies (mAb) were from PharMingen (San Diego, CA). Mouse anti-human TCRzeta mAb (6B10.2) was from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Rabbit anti-rat immunoglobulin and peroxidase-conjugated rabbit anti-mouse immunoglobulin were from Dakopatts A/S (Glostrup, Denmark). The phorbol-ester phorbol 12,13-dibutyrate (PDB) was from Sigma.

Constructs, Transfection, and Western Blotting-- The truncated CD3gamma and the chimeric CD4/CD3gamma and CD16/CD3gamma molecules were constructed as described previously (14, 15, 18) by polymerase chain reaction using the plasmids pJ6T3gamma -2 (19), pCD-L3T4.25 (20), or Fcgamma RIII-2 (21) as templates. Mutations were confirmed by DNA sequencing. Transfections were performed using the Bio-Rad Gene Pulser at a setting of 270 V and 960 microfarad with 40 µg of plasmid/2 × 107 cells. After 3-4 weeks of selection, G418-resistant clones were expanded and maintained in medium without G418. Western blotting was performed as described previously (22).

Receptor Internalization and Recycling-- To determine the spontaneous internalization rates, cells were incubated in RPMI 1640 + 10% FCS at a cell density of 2 × 105 cells/ml at 37 °C or 4 °C with PE-conjugated anti-CD3epsilon , anti-CD16, or anti-CD4 mAb. At the time indicated, aliquots of cell suspension were washed in ice-cold RPMI 1640 + 10% FCS, divided in two equal parts, and subsequently treated with 300 µl of 0.5 M NaCl, 0.5 M acetic acid, pH 2.2, for 10 s or left untreated. The fluorescence of the cells was measured by flow cytometry in a FACSCalibur flow cytometer (Becton Dickinson, Mountain View, CA). The percentage of internalized mAb to cell surface bound mAb was subsequently calculated using the equation: ((HAR - CAR)/CT) × 100%, where HAR is the mean fluorescence intensity (MFI) of acid-treated cells incubated at 37 °C, CAR is the MFI of acid treated cells incubated at 4 °C, and CT is the MFI of untreated cells incubated at 4 °C. For each construct at least three different clones were analyzed.

For PKC-induced receptor internalization, cells were adjusted to 2 × 105 cells/ml medium (RPMI 1640 + 10% FCS) and incubated at 37 °C with various concentrations of the phorbol ester PDB. At the time indicated, cells were transferred to ice-cold PBS containing 2% FCS and 0.1% NaN3 and washed twice. The cells were stained directly with PE-conjugated anti-CD3epsilon or anti-CD16 mAb and analyzed by flow cytometry. MFI was recorded and used in the calculation of percent mAb binding: (MFI of phorbol ester treated cells) divided by (MFI of untreated cells) × 100%. For each construct at least three different clones were analyzed.

    RESULTS AND DISCUSSION
Top
Abstract
Introduction
Procedures
Results & Discussion
References

The CD16/CD3gamma Chimera Is Stably Expressed at the Cell Surface in Association with TCRzeta -- We and others have previously demonstrated that the CD3gamma L-based motif is constitutively active in chimeric CD4/CD3gamma and Tac/CD3gamma molecules independently of phosphorylation (13, 15). The active L-based motif results in very low expression of these chimeras at the cell surface. To determine whether the TCRzeta chain had the potential to mask the CD3gamma L-based motif and thereby allow stable receptor cell surface expression, we took advantage of the observation that the Fc receptor Fcgamma RIIIA-alpha chain (CD16) is only expressed at the cell surface of Jurkat cells in association with TCRzeta (23). In contrast to CD16, CD4 is expressed as a monomer at the cell surface (24). By comparing chimeric CD4/CD3gamma and CD16/CD3gamma molecules either with or without an intact CD3gamma L-based motif, this enabled us specifically to examine if and how the TCRzeta chain influenced the activity of the CD3gamma L-based motif. Six different constructs were made. CD3gamma -tS126 and CD3gamma -tP133 coded for the CD3gamma chain with a truncated cytoplasmic tail immediately before and after the L-based motif, respectively. CD4/CD3gamma -tS126 and CD4/CD3gamma -tP133 coded for chimeric molecules composed of the extracellular and transmembrane domains of CD4 and the cytoplasmic tail of CD3gamma truncated immediately before and after the L-based motif, respectively. CD16/CD3gamma -tS126 and CD16/CD3gamma -tP133 coded for chimeric molecules composed of the extracellular and transmembrane domains of CD16 and the cytoplasmic tail of CD3gamma truncated immediately before and after the L-based motif, respectively (Fig. 1A). These constructs were separately transfected into the CD3gamma negative Jurkat variant JGN (10) and G418-resistant transfectants were tested for cell surface expression of the transfected molecules by FACS analysis. As shown in Fig. 1B, the TCR and the CD16/CD3gamma chimera were all highly expressed at the cell surface independent of the presence or absence of the CD3gamma L-based motif. In agreement with previous studies, the CD4/CD3gamma -tS126 chimera was highly expressed, whereas the CD4/CD3gamma -tP133 chimera with an active CD3gamma L-based motif was only weakly expressed at the cell surface although highly expressed intracellularly (Fig. 1B and data not shown) (15). To analyze whether the chimeras actually associated with TCRzeta , cells were lysed in digitonin lysis buffer and immunoprecipitated with either anti-CD4 or anti-CD16 mAb. The precipitates were resolved by SDS-polyacrylamide gel electrophoresis, and Western blot analysis was performed using the anti-TCRzeta mAb. As shown in Fig. 1C, TCRzeta clearly co-precipitated with the CD16/CD3gamma chimeras but did not co-precipitate with the CD4/CD3gamma chimeras.


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  		Fig. 1.   The CD16/CD3gamma chimera is stably expressed at the cell surface in association with TCRzeta . A, schematic representation of the amino acid sequences in the cytoplasmic tails of the truncated CD3gamma , CD4/CD3gamma , and CD16/CD3gamma chimeric molecules. B, cell surface expression of the TCR, the CD4/CD3gamma , and the CD16/CD3gamma chimeric molecules. Transfectants were incubated with PE-conjugated anti-CD3epsilon , anti-CD4, and anti-CD16 mAb, respectively, and analyzed by flow cytometry. The FACS profiles of the transfectants are shown in black. In each histogram, the FACS profile of the recipient cell line JGN stained with the corresponding mAb is shown (dotted line). The ordinate gives the relative cell number, and the abscissa gives the fluorescence intensity in a logarithmic scale in arbitrary units. C, Western blot of JGN (lanes 1 and 4), CD4/CD3gamma -tS126 (lane 2), CD4/CD3gamma -tP133 (lane 3), CD16/CD3gamma -tS126 (lane 5), and CD16/CD3gamma -tP133 (lane 6) cells precipitated with anti-CD4 (lanes 1-3) or anti-CD16 (lanes 4-6) mAb. The precipitated molecules were separated by SDS-polyacrylamide gel electrophoresis under nonreducing conditions, transferred to nitrocellulose membranes, and analyzed by incubation with the anti-TCRzeta mAb 6B10.2. The position of the TCRzeta dimer is indicated.

These experiments demonstrated that in the absence of the CD3gamma L-based motif both the TCR, the CD4/CD3gamma , and the CD16/CD3gamma chimeras were highly expressed at the cell surface independent of their capacity to associate with TCRzeta . In contrast, in the presence of an intact CD3gamma L-based motif only molecules capable of forming association with TCRzeta were expressed at the cell surface. Because the CD4/CD3gamma -tP133 and CD16/CD3gamma -tP133 chimeras had identical cytoplasmic tails with an intact CD3gamma L-based motif and only differed intracellularly by their ability to associate with the TCRzeta chain, these observations suggested that TCRzeta masked and thereby inactivated the CD3gamma L-based motif of the CD16/CD3gamma -tP133 chimera.

The CD3gamma L-based Motif Is Inactive in CD16/CD3gamma -TCRzeta Complexes but Can Be Activated Following PKC Activation-- We have previously demonstrated that CD4/CD3gamma chimeras with an inactive CD3gamma L-based motif have low spontaneous internalization rates and are highly expressed at the cell surface, whereas CD4/CD3gamma chimeras with an active CD3gamma L-based motif have high spontaneous internalization rates and are weakly expressed at the cell surface (15). To analyze whether the CD3gamma L-based motif in the CD16/CD3gamma -tP133-TCRzeta complex was active at the cell surface, the spontaneous internalization rate was determined. As expected, the CD4/CD3gamma -tP133 chimera had a high spontaneous internalization rate reflecting the active CD3gamma L-based motif present in this chimera, and the TCR-tP133 had a low spontaneous internalization rate reflecting the inactive CD3gamma L-based motif in the completely assembled TCR. Like the TCR-tP133, the CD16/CD3gamma -tP133-TCRzeta complex had a low spontaneous internalization rate, indicating that the CD3gamma L-based motif in the CD16/CD3gamma -tP133-TCRzeta complex was inactive (Fig. 2A). Likewise, the CD4/CD3gamma -tS126 that did not contain the CD3gamma L-based motif had a low spontaneous internalization rate.


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  		Fig. 2.   The CD3gamma L-based motif is inactive in CD16/CD3gamma -TCRzeta complexes but can be activated following PKC activation. A, spontaneous internalization of the TCR and chimeric CD4/CD3gamma and CD16/CD3gamma molecules. The percentage of internalized mAb to cell surface bound mAb was calculated as described under "Experimental Procedures." B, receptor down-regulation of cells incubated with different concentrations of the PKC activator PDB for 1 h. Down-regulation was determined by staining the cells with PE-conjugated anti-CD3epsilon (TCR-tP133) or anti-CD16 (CD16/CD3gamma -tP133) mAb followed by flow cytometry comparing MFI of PDB-treated cells with MFI of untreated cells.

Following PKC-induced phosphorylation the CD3gamma L-based motif in the context of the TCR is activated. This results in an increased internalization rate and a down-regulation of the TCR from the cell surface (14, 25). To analyze whether the CD3gamma L-based motif in the CD16/CD3gamma -tP133-TCRzeta complex could be activated following PKC activation, cells were treated with the phorbol ester PDB and subsequently analyzed for receptor expression. Interestingly, similar to the TCR-tP133, the CD16/CD3gamma -tP133-TCRzeta complex was down-regulated from the cell surface following PKC activation (Fig. 2B). An approximately 5-fold higher PBD concentration was required to induce down-regulation of the CD16/CD3gamma -tP133-TCRzeta complex as compared with the TCR, which might indicate that the CD3gamma L-based motif was not as accessible for PKC in the CD16/CD3gamma -tP133-TCRzeta complex as in the TCR-tP133.

Taken together, these experiments demonstrated that the CD3gamma L-based motif is constitutively active in monomeric CD4/CD3gamma -tP133 chimeras but inactive in CD16/CD3gamma -tP133-TCRzeta complexes. Furthermore, as seen for the CD3gamma L-based motif in the TCR, the CD3gamma L-based motif in the CD16/CD3gamma -tP133-TCRzeta complex was activated following phosphorylation. These observations strongly indicated that the TCRzeta chain allows stable cell surface expression of receptors containing CD3gamma L-based motifs by masking this motif and that phosphorylation directly influences the interaction between CD3gamma and TCRzeta in both TCR and CD16/CD3gamma -TCRzeta complexes. Previous studies have demonstrated that the cytoplasmic tails of Tialpha , Tibeta , CD3gamma , CD3delta , and CD3epsilon are dispensable for TCR expression (18, 26-28). Thus, neither of these chains seems to be involved in masking any potential internalization/degradation motifs in the TCR. In contrast, to our knowledge the shortest TCRzeta chain that allows TCR cell surface expression previously published contained a cytoplasmic tail of 26 amino acids (29, 30). These studies support our present results. Experiments with successive truncations of the TCRzeta chain are presently being performed to determine the minimal length of the TCRzeta cytoplasmic tail that allows TCR expression.

    ACKNOWLEDGEMENTS

We thank Drs. M. J. Crumpton, J. V. Ravetch, and D. R. Littman for the plasmids pJ6T3gamma -2, Fcgamma RIII-2, and pCD-L3T4.25, respectively. The technical help of Bodil Nielsen is gratefully acknowledged.

    FOOTNOTES

* This work was supported by The Danish Cancer Society, The Novo Nordisk Foundation, The Danish Medical Research Council, The Danish Natural Science Research Council, Director Ib Henriksens Foundation, and Gerda and Aage Haensch's Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Recipient of post-doctoral fellowship from The Danish Medical Research Council.

§ Member of The Biotechnology Center for Cellular Communication. To whom correspondence should be addressed: Inst. of Medical Microbiology and Immunology, University of Copenhagen, Panum Inst., Bldg. 18.3, Blegdamsvej 3C, DK-2200 Copenhagen, Denmark. Tel.: 45-3532-7880; Fax: 45-3532-7881; E-mail: cgtcr{at}biobase.dk.

The abbreviations used are: TCR, T cell receptor; L-based, leucine-based; PKC, protein kinase C; PE, phycoerythrin; PDB, phorbol 12,13-dibutyrate; MFI, mean fluorescence intensity; mAb, monoclonal antibodies; FCS, fetal calf serum; FACS, fluorescence-activated cell sorter.
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Abstract
Introduction
Procedures
Results & Discussion
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Identification and Functional Characterization of the {zeta}-Chain Dimerization Motif for TCR Surface Expression
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Modification of the T Cell Antigen Receptor (TCR) Complex by UDP-glucose:Glycoprotein Glucosyltransferase. TCR FOLDING IS FINALIZED CONVERGENT WITH FORMATION OF alpha beta delta epsilon gamma epsilon COMPLEXES
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