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The Journal of Immunology, 2008, 180, 3642 -3646
Copyright © 2008 by The American Association of Immunologists, Inc.
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Cutting Edge: A Naturally Occurring Mutation in CD1e Impairs Lipid Antigen Presentation1

Sylvie Tourne2,*,{ddagger},§, Blandine Maitre*,{dagger},{ddagger},§, Anthony Collmann, Emilie Layre||, Sabrina Mariotti, François Signorino-Gelo*,{ddagger},§, Caroline Loch#, Jean Salamero**,{dagger}{dagger}, Martine Gilleron||, Catherine Angénieux*,{ddagger},§, Jean-Pierre Cazenave{dagger},{ddagger},§, Lucia Mori, Daniel Hanau*,{ddagger},§, Germain Puzo||, Gennaro De Libero and Henri de la Salle2,*,{ddagger},§

* Unité 725 "Biology of Human Dendritic Cells" and {dagger} Unité 311, Institut National de la Santé et de la Recherche Médicale (INSERM), Strasbourg, France; {ddagger} Etablissement Français du Sang-Alsace, Strasbourg, France; § Université Louis-Pasteur, Strasbourg, France; Experimental Immunology, Department of Research, Basel University Hospital, Basel, Switzerland; || Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 5089, Department of Molecular Mechanisms of Mycobacterial Infections, Toulouse, France; # Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM, Université Louis-Pasteur, Illkirch-Graffenstaden, France; and ** Imaging Center and {dagger}{dagger} "Molecular Mechanisms of Intracellular Transport," UMR144 CNRS, Institut Curie, Paris, France


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Conclusion
 Disclosures
 References
 
The human CD1a–d proteins are plasma membrane molecules involved in the presentation of lipid Ags to T cells. In contrast, CD1e is an intracellular protein present in a soluble form in late endosomes or lysosomes and is essential for the processing of complex glycolipid Ags such as hexamannosylated phosphatidyl-myo-inositol, PIM6. CD1e is formed by the association of β2-microglobulin with an {alpha}-chain encoded by a polymorphic gene. We report here that one variant of CD1e with a proline at position 194, encoded by allele 4, does not assist PIM6 presentation to CD1b-restricted specific T cells. The immunological incompetence of this CD1e variant is mainly due to inefficient assembly and poor transport of this molecule to late endosomal compartments. Although the allele 4 of CD1E is not frequent in the population, our findings suggest that homozygous individuals might display an altered immune response to complex glycolipid Ags.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Conclusion
 Disclosures
 References
 
In humans, CD1a–d present lipids to T cells (1). They acquire self-lipid ligands in the endoplasmic reticulum (ER),3 where they are assembled, and lipid Ags in the endosomal compartments, where they cycle through after a transit from the cell surface (2). CD1e also participates in the presentation of lipids to T cells, but not as an Ag-presenting molecule. CD1e never transits through the plasma membrane but is directly targeted from Golgi compartments to early endosomes before reaching late endosomes and lysosomes (3). In these latter compartments CD1e facilitates the processing of complex glycolipids, which is required for their presentation by CD1b molecules. In particular, CD1e is essential in the processing of hexamannosylated phosphatidyl-myo-inositol (PIM6) by the lysosomal {alpha}-mannosidase (4).

CD1, like MHC class I molecules, is composed of a transmembrane {alpha}-chain that noncovalently associates with the β2-microglobulin (β2m). The {alpha}-chain folds in three structural {alpha} domains ({alpha}1–3), with the {alpha}1 and {alpha}2 domains delimiting a hydrophobic pocket-containing groove in which lipid ligands bind. For CD1e, the {alpha}-chain is cleaved between the {alpha}3 and the transmembrane domains in late endosomal compartments, generating by this way soluble CD1e, which represents the CD1e active form (4, 5). The human CD1 genes are poorly polymorphic. Only two alleles have been described for CD1A, B, C, and D (6, 7), the polymorphism of CD1B and C being silent (6, 7). CD1E is the most polymorphic CD1 gene, six alleles having been reported (6, 8, 9). Among individuals from diverse ethnic backgrounds, alleles 1 and 2 display a frequency of 49 and 51%, respectively (6), whereas the four other alleles have been described once (8, 9). The polymorphic nucleotides are located in exons 2 or 3 of the CD1E gene, encoding the {alpha}1 and {alpha}2 domains, respectively (see Fig. 1) (6, 8, 9).


Figure 1
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  		FIGURE 1. CD1e residues affected by the polymorphism of the CD1E gene. A, Model of the three-dimensional structure of the {alpha}1 and {alpha}2 domains of CD1e-2 and the locations of the residues affected by the polymorphism of CD1E. B, Nature of the amino acids located at positions 102, 106, 149, 164, and 194 in the sequences of the different CD1e variants.

 
The impact of the polymorphism of the CD1 gene on the structure and function of the encoded protein has been poorly addressed. The products of CD1A alleles are similarly expressed on the cell surface and display similar structural characteristics (10), whereas no significant correlation between the CD1 genotype and susceptibility to Mycobacterium malmoense pulmonary disease (11) or chronic dysimmune neuropathies (12) could be inferred.

In this study, we examine the impact of the polymorphism of CD1E gene on the function of the encoded proteins.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Conclusion
 Disclosures
 References
 
DNA constructs and cell transfection

The cDNAs encoding the CD1e variants were derived from CD1e-2 cDNA by PCR-based mutagenesis methods. These cDNA were cloned in the pEGFP-N3 expression vector (Clontech) and transfected, as previously described (5), into the melanoma M10 cells already transfected, or not, with CD1b cDNA. The cDNA encoding recombinant soluble (rs) CD1e-4, from residue Asp21 to residue Ser305, was cloned in a pMTV5His plasmid (Invitrogen Life Technologies) and coexpressed with human β2m in Drosophila S2 cells as described (4).

Antibodies

The anti-CD1e mAb VIIC7, 1.22 and 20.6, have been described (5). Polyclonal IgGs specific for the denatured CD1e H chain were obtained by immunizing a rabbit with a recombinant protein consisting of the CD1e {alpha}1, {alpha}2, and {alpha}3 domains fused to GST. An anti-CD1b mAb (clone 4A7.6) was purchased from Beckman Coulter and an anti-CD63 mAb (clone H5C6) was conjugated to Alexa Fluor 488 (5). Cyanine 3- or PE-conjugated F(ab')2 specific for mouse IgG was obtained from respectively Jackson ImmunoResearch or DakoCytomation. HRP-conjugated polyclonal Abs specific for rabbit and mouse Ig were purchased from Jackson ImmunoResearch and DakoCytomation, respectively. IgG1 (clone 679.1 Mc7) and IgG2a (clone U7.27) mAbs from Beckman Coulter were used as isotypic controls and normal mouse serum was obtained from Rockland.

Immunostaining and analyses

Cells, fixed and permeabilized for intracellular labeling, were stained as described (5) and analyzed on a FACSCalibur flow cytometer (BD Biosciences) or under a Leica SP5 AOBS confocal microscope (Leica Microsystems). The specific median fluorescence intensities (MFIs) were obtained by subtracting the MFI of cells stained with an IgG isotype-matched control from the MFI of cells stained with the Ab of interest. Colocalization was quantified as described (3).

Cell extracts

Cells, labeled or not with [35S]methionine and cysteine as previously described (5), were resuspended in lysis buffer containing 1% Triton X-100, Nonidet P-40, digitonin or CHAPS, 150 mM NaCl, 20 mM Tris (pH 8), and a mixture of protease inhibitors (Complete Mini; Roche Applied Science) for 30 min on ice and then cleared by a 10-min centrifugation at 13,000 x g.

Immunoprecipitations and Western blotting (WB)

Immunoprecipitations and treatment with glycosidases were performed as described (5) before separation on SDS-PAGE. When necessary, gels were fixed, dried, and exposed to autoradiography or to PhosphorImager screens. The radioactive signals were quantified by Quantity One software after scanning on a Typhoon Trio PhosphorImager (GE-Healthcare). For WB, proteins were transferred to nitrocellulose membranes (Bio-Rad) and CD1e molecules were detected according to the usual protocols using West Pico chemiluminescent substrate (Perbio Science).

Ag presentation assays

APCs (3 x 104 cells) were preincubated for 2 h at 37°C with monosialoganglioside (GM1; Matreya) or Mycobacterium tuberculosis PIM6, extracted, and purified according to the procedure described in Ref. 13 . T cell clones (105 cells in triplicate) GG33A recognizing the CD1e-independent Ag GM1 (14) and DL15A30 recognizing PIMs in a CD1b-restricted manner, obtained as described in Ref. 4 , were then added and, after 36 h, GM-CSF release was measured by ELISA (R&D Systems), as well as IFN-{gamma} release (data not shown).

In vitro mannosidase digestion assays

In vitro digestion assays of PIM6 by mannosidase and mass spectrum analyses were performed as previously described (4).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Conclusion
 Disclosures
 References
 
CD1e with P194 is not able to assist CD1b presentation of PIM6 Ag

Human CD1e is essential for the lysosomal processing of PIM6 into antigenic molecule(s) presented by CD1b (4). This function was initially described for the product of CD1E-2 gene, the most common allele (6). In this study we investigated whether the products of the five other alleles of CD1E gene display similar properties.

We constructed cDNAs encoding CD1e molecules with residues specifically found in the proteins encoded by the alleles 1, 2, 3, 4, 5, and 6 of CD1E, referred to in this paper as CD1e-1, CD1e-2, CD1e-3, CD1e-4, CD1e-5, and CD1e-6, respectively (Fig. 1B). M10 cells expressing CD1b (M10-CD1b), which have already been used as APCs to study CD1e function (4), were stably transfected with each of these cDNAs. Clones expressing the CD1e variants were selected by immunofluorescence staining of fixed, permeabilized cells with the conformation-dependent mAbs 1.22 and 20.6, previously raised and selected using CD1e-2 molecules (5). FACS analyses showed that all of the variants were recognized by 1.22 and all but CD1e-3 were recognized by 20.6 (data not shown), which means that arginine 164, substituted by a tryptophan in CD1e-3, contributes to the epitope recognized by the mAb 20.6. These analyses also showed that all of the clones displayed a similar MFI of staining with the mAb 1.22, indicating that they expressed similar amounts of CD1e (data not shown).

These doubly transfected cells were used as APCs for the CD1b-restricted presentation of PIM6 to the specific T cell clone DL15A30. The GM-CSF release of T cells in response to different concentrations of Ag revealed that cells coexpressing CD1b and CD1e-1, CD1e-2, CD1e-3, CD1e-5, or CD1e-6 were able to present PIM6 to T cells in a dose-dependent manner (Fig. 2A). In contrast, PIM6 presentation by M10-CD1b-CD1e-4 cells was significantly reduced and comparable to that obtained with single CD1b-transfected APCs (Fig. 2A). Similar data were obtained by measuring IFN-{gamma} release and by using another CD1b-restricted and PIM6-specific T cell clone (data not shown).


Figure 2
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  		FIGURE 2. A, Assistance of CD1e-4 in PIM6 presentation to T cells. M10 (not transfected), M10-CD1b, M10-CD1e-2, M10-CD1b-CD1e-1, -CD1e-2, -CD1e-3, -CD1e-4, -CD1e-5, or -CD1e-6 cells were preincubated with different doses of PIM6 or GM1 before addition of DL15A30 or GG33A T cells, respectively. GM-CSF release was used to quantify the T cells. The experiments illustrated have been performed twice with the same results. B, Assistance of rsCD1e-4 in the in vitro digestion of PIM6 by {alpha}-mannosidase ({alpha}-Man). PIM6 was incubated for 1 h at 37°C with jack bean {alpha}-mannosidase in the presence or absence of rsCD1e-4, after which PIMs were extracted and analyzed by MALDI-TOF mass spectrometry. Relative abundance of the different PIM glycoforms is presented.

 
The poor capacity of CD1e-4-expressing cells to assist PIM6 presentation was not due to a lower expression of CD1b, because FACS analyses showed that the specific MFIs of M10-CD1b-CD1e-4 and -CD1e-2 cells stained with an anti-CD1b mAb were comparable (346 and 225, respectively, with M10 cells having a specific MFI of 0.4) (data not shown). This reduced T cell response was also not caused by a general defect in Ag presentation of CD1e-4 expressing cells, as these cells very efficiently presented the CD1e-independent Ag GM1 to the specific CD1b-restricted T cell clone GG33A (Fig. 2A).

To determine whether the inability of CD1e-4 to assist PIM6 presentation was due to incapacity of the protein to participate in the processing of PIM6 into PIM2 by {alpha}-mannosidase, we produced rsCD1e-4 molecules in insect cells. The activity of rsCD1e-4 in the in vitro enzymatic digestion of PIM6 by {alpha}-mannosidase is reported in Fig. 2B. MALDI-TOF analyses showed that in the presence of rsCD1e-4, as previously reported for rsCD1e-2 (4), {alpha}-mannosidase was able to generate PIM2 molecules. Thus, the rsCD1e-4 produced in insect cells was biochemically functional in vitro.

CD1e-4 exhibits a singular intracellular fate

Because CD1e-4 appeared to be active in biochemical but not in Ag presentation assays, we examined whether CD1e-4 underwent a different intracellular fate as compared with the other CD1e variants. We first established that the other CD1e variants displayed subcellular localization (in late endosomal compartments) and maturation processes (cleavage and resistance to Endo-H) similar to those of CD1e-2 (data not shown), and we then chose to compare CD1e-1 and CD1e-4, which only differ at residue 194 (Fig. 1B).

We first showed that CD1e-4 remained strictly intracellular, as does CD1e-1 (data not shown). To examine the intracellular localization of the protein, fixed and permeabilized transfected cells were costained with anti-CD1e and anti-CD63 mAbs and analyzed by confocal microscopy. CD1e-4 colocalized with CD63 molecules and hence was present in late endosomal compartments, like CD1e-1 (Fig. 3A). However, quantitative measurements revealed that CD1e-4 colocalized with CD63 about four times less than CD1e-1 did (Fig. 3B).


Figure 3
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  		FIGURE 3. Subcellular distribution of CD1e-4. A, Fixed, permeabilized M10-CD1b-CD1e-1 or -CD1e-4 cells were stained with the mAb 20.6 and revealed with cyanine 3-conjugated polyclonal Abs and an Alexa Fluor 488-conjugated anti-CD63 mAb before analysis by confocal microscopy. Insets are a focal view of a part of the cell. B, The colocalization of CD1e and CD63 was quantified by counting CD63 and CD1e single and double positive structures in seven M10-CD1b-CD1e-1 or -CD1e-4 cells as previously described (3 ). The total numbers of double positive organelles in CD1e-1- or CD1e-4-expressing cells were 900 and 160, respectively. The histograms represent the means of the ratios of the numbers of double positive (DP) to single positive vesicles (DP+CD1e+ and DP+CD63+, respectively). The SD for each condition is indicated.

 
During its intracellular transport, CD1e becomes Endo-H resistant in the Golgi apparatus and soluble in the late endosomal compartments. To investigate the biochemical maturation of CD1e-4, transfected cells were metabolically labeled for 45 min, chased for 0, 4, or 8 h, and lysed in buffer containing Triton X-100, after which CD1e molecules were immunoprecipitated with the mAb 20.6, treated or not with PNGase F or Endo-H, and separated by SDS-PAGE. In contrast to CD1e-1, which was progressively converted into a cleaved form during chase, cleaved CD1e-4 remained undetectable after 4 h (Fig. 4A) and up to 8 h of chase (data not shown). Moreover, when CD1e-4 was immunoprecipitated with the mAb 20.6 from detergent-solubilized extracts of transfected cells, no cleaved proteins were detected by WB using polyclonal rabbit IgGs specific for the denatured luminal part of CD1e. These Abs nevertheless revealed the uncleaved form, as did the mAb VIIC7 (Fig. 4B). In contrast, cleaved CD1e molecules were detected in control experiments using extracts from cells expressing CD1e-2 or CD1e-1 (Fig. 4B). Pulse-chase experiments also revealed that unlike CD1e-1, which became Endo-H resistant during chase, CD1e-4 remained Endo-H sensitive (Fig. 4A). Nonetheless, WB analyses of CD1e, immunoprecipitated from detergent-solubilized extracts of transfected cells, demonstrated that at least a small fraction of CD1e-4 molecules became Endo-H resistant (Fig. 4C), consistent with its detection in CD63+ compartments (Fig. 3A). Similar results were obtained when pulse-chase experiments were performed using the mAb 1.22 instead of 20.6 or CHAPS instead of Triton X-100 (data not shown).


Figure 4
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  		FIGURE 4. Maturation of CD1e-4. A, M10-CD1b-CD1e-1 or -CD1e-4 cells were metabolically labeled for 45 min and chased for 0 or 4 h. CD1e molecules were immunoadsorbed on the mAb 20.6, digested with PNGase F (F) or Endo-H (H) or not (–) and separated by SDS-PAGE. The positions of the uncleaved and cleaved CD1e forms are indicated by an arrowhead and an arrow, respectively. The positions of Endo-H-sensitive and Endo-H-resistant species are indicated by a larger arrowhead followed by s (sensitive) and r (resistant), respectively (at 4-h chase time point). B, Cell extracts were prepared from M10-CD1b (–) or M10-CD1b-CD1e-1 (1), CD1e-2 (2), or CD1e-4 (4), and CD1e molecules were immunoadsorbed using the mAb 20.6. Uncleaved forms were revealed by WB with the mAb VIIC7, while uncleaved and cleaved forms were detected with polyclonal rabbit IgGs specific for the denatured luminal part of CD1e. Symbols are defined in A. C, Cell extracts were prepared from M10-CD1b-CD1e-1 or -CD1e-4 cells and uncleaved CD1e molecules were immunoadsorbed with the mAb VIIC7, digested with PNGase F (F) or Endo-H (H) or not (–) and analyzed by WB using the mAb VIIC7. Symbols are defined in A.

 
Altogether, these observations suggested that either only small amounts of CD1e-4 reach late endosomal compartments or that CD1e-4 is degraded in these compartments.

CD1e assembly and traffic are affected by the L194P substitution

To study the stability of CD1e-4 in late endosomal compartments, M10-CD1b-CD1e-1 or -CD1e-4 cells were metabolically labeled during 5 h in the absence or presence of bafilomycin, which blocks acidification of the late endosomal compartments. Immunoprecipitation of CD1e with the mAb 20.6 followed or not by a treatment with glycosidases showed that uncleaved Endo-H resistant forms of both CD1e-1 and CD1e-4 accumulated in cells treated with bafilomycin (Fig. 5A). Nevertheless, the Endo-H resistant CD1e-4 forms were far less abundant than the CD1e-1 ones, suggesting that only small amounts of CD1e-4 reach endosomes (Fig. 5A).


Figure 5
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  		FIGURE 5. Assembly and export of CD1e-4 to late endosomal compartments. A, M10-CD1b-CD1e-1 or -CD1e-4 cells were metabolically labeled in the presence or absence of bafilomycin (0.1 µM). After 5 h, CD1e molecules were immunoadsorbed with the mAb 20.6, digested with PNGase F (F) or Endo-H (H) or not (–) and separated by SDS-PAGE. Symbols are defined in Fig. 4A. B, M10-CD1b (–) cells or M10-CD1b-CD1e-1 (4) or M10-CD1b-CD1e-4 (4) cellswere metabolically labeled for 1 h and cell extracts were prepared in Triton X-100, Nonidet P-40, digitonin, or CHAPS. CD1e molecules were immunoadsorbed with the mAb VIIC7, separated by SDS-PAGE, and exposed for autoradiography. To determine the {alpha}-chain/β-2M ratios, gels were exposed to PhosphorImager screens.

 
This defect might result from an altered association of the CD1e {alpha}-chain with β2m in the ER. Indeed, the exit of CD1a, CD1b, and CD1c from the ER has been reported to be strictly dependent on the association of CD1 {alpha}-chains with β2m (15), while only a fraction of newly synthesized CD1d H chains reach the plasma membrane not associated with β2m (16). In agreement with this hypothesis, fewer β2m molecules were coimmunoprecipitated with the CD1e-4 {alpha}-chain as compared with the CD1e-1 {alpha}-chain using the mAb VIIC7 (Fig. 5B) or 20.6 (data not shown). This difference was also apparent when Nonidet P-40, digitonin, or CHAPS was used as the detergent (Fig. 5B).

The crystallographic resolution of other CD1 molecules provides no argument in favor of a direct participation of leucine 194 in the binding of CD1e to β2m (17). Nevertheless, proline is a residue known to potentially affect the conformation of proteins by introducing an elbow into the structure. Owing to the proximity of residue 194 to the {alpha}3 domain, which interacts with β2m, the association of β2m with the CD1e-4 {alpha}-chain might be affected. Next to residue 194, at position 193, is a conserved aromatic amino acid, a phenylalanine that contributes to the A' pocket of the CD1 binding groove. As CD1e binds lipids (4), the L194P substitution could affect the stereo arrangement of this aromatic residue and, consequently, the capture of an endogenous lipid required for the appropriate assembly and stability of CD1e molecules in the ER.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Conclusion
Disclosures
 References
 
In summary, the polymorphism of the CD1E allele 4 represents the first example of a functional defect in the family of CD1 molecules. It alters the assembly and, consequently, the intracellular transport and function of the encoded molecule. Because the functional impairment resulting from this polymorphism relates to the capacity of the CD1e molecule to participate in the immune response to complex glycolipids, it is tempting to speculate that individuals homozygous for the allele 4 of CD1E might display an altered immune response to M. tuberculosis lipid Ags requiring endosomal processing. It will be important to determine whether the polymorphism of the CD1E gene represents a factor of susceptibility to human diseases involving the immune response to complex glycolipid Ags.


   Acknowledgments
 
We are especially grateful to J. Mulvihill for excellent editorial assistance. We also thank the members of the RIO-Cell and Tissue Imaging Facility of UMR 144, CNRS-Institut Curie for their help with imaging approaches.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Conclusion
 Disclosures
References
 
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 Institut National de la Santé et de la Recherche Médicale, Etablissement Français du Sang-Alsace and Agence Nationale de Recherche Microbiologie-Maladie Emergentes (ANR-05-MIME-006), the European Union funded TB-VAC tuberculosis vaccine project (LSHP-CT-2003-503367), Swiss National Fund Grant 3100A0-109918, and the Basel Cancer League (Krebsliga Beider Basel). B.M. was the recipient of a grant from Association de Recherche et de Développement en Médecine et en Santé Publique (ARMESA). Back

2 Address correspondence and reprint requests to Dr. Sylvie Tourne or Dr. Henri de la Salle, Institut National de la Santé et de la Recherche Médicale, Unité 725, Etablissement Français du Sang-Alsace, 10 Rue Spielmann, 67065 Strasbourg Cedex, France. E-mail addresses: sylvie.tourne{at}efs-alsace.fr and henri.delasalle{at}efs-alsace.fr Back

3 Abbreviations used in this paper: ER, endoplasmic reticulum; β2m, β2-microglobulin; Endo-H, endoglycosidase H; GM1, monosialoganglioside GM1; MFI, median fluorescence intensity; PIM, phosphatidyl-myo-inositol-mannoside; PIM6, hexamannosylated phosphatidyl-myo-inositol; PNGase F, peptide N-glycosidase F; rs, recombinant soluble (prefix); WB, Western blotting. Back

Received for publication November 5, 2007. Accepted for publication January 25, 2008.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Conclusion
 Disclosures
 References
 

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M. I. Zimmer, H. P. Nguyen, B. Wang, H. Xu, A. Colmone, K. Felio, H.-J. Choi, P. Zhou, M.-L. Alegre, and C.-R. Wang
Polymorphisms in CD1d affect antigen presentation and the activation of CD1d-restricted T cells
PNAS, February 10, 2009; 106(6): 1909 - 1914.
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