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The Journal of Immunology, 2000, 165: 632-636.
Copyright © 2000 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Chandra, a Novel Four-Transmembrane Domain Protein Differentially Expressed in Helper Type 1 Lymphocytes

Chandrasekar Venkataraman, Gabriele Schaefer and Ulrike Schindler1

Tularik, South San Francisco, CA 94080


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Development of naive Th cells into Th1 and Th2 effector populations requires coordinated expression of a complex set of genes. In this study, we have identified a novel four-transmembrane domain protein, Chandra, that is differentially expressed in Th1 cells. Chandra expression is observed in STAT4- and IFN-{gamma}-deficient mice, indicating that Chandra is not an IL-12- or IFN-{gamma}-responsive gene. Interestingly, Chandra mRNA is detected in anti-CD3-activated T cells from STAT6-deficient mice in the absence of any differentiation conditions. Furthermore, neutralization of IL-4 signaling is sufficient to induce transcription of Chandra in anti-CD3-activated T cells from wild-type mice, demonstrating that STAT6 signaling is required to repress Chandra expression in activated T cells and Th2 subsets. This is the first demonstration of a differentially expressed four-transmembrane domain protein in Th1 cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
During chronic infections, stimulation of naive Th cells results in the development of at least two phenotypically and functionally distinct effector populations, Th1 and Th2 lymphocytes (1, 2). Th1 cells produce IFN-{gamma} and IL-2, which are commonly associated with cell-mediated immune responses against various intracellular pathogens, organ-specific autoimmune diseases, and delayed-type hypersensitivity (2). Th2 cells produce cytokines such as IL-4, IL-5, IL-6, IL-10, and IL-13 that are crucial to control extracellular helminthic infections. In addition, an imbalance of Th2 cytokines is observed in various atopic and allergic diseases, which are usually accompanied by increased production of IgG1 and IgE and activation of eosinophils and mast cells (1).

Cytokines such as IL-12 and IL-4 have dominant roles in determining the outcome of Th differentiation into Th1 and Th2 subsets, respectively (3). Following IL-12 binding to its cognate receptor, STAT4 is activated, which provides crucial signals for IFN-{gamma} production by Th1 cells. In contrast, IL-4-dependent STAT6 activation is required for the development of Th2 cells (3). The essential functions of STAT4 and STAT6 in the differentiation of Th cells have been demonstrated using gene-targeting studies (4, 5, 6, 7). STAT4-deficient mice are defective in Th1 differentiation and do not respond to intracellular pathogens such as Listeria monocytogenes (7). In contrast, STAT6-deficient mice have an impaired ability to produce IL-4-secreting Th2 cells, fail to expel intestinal helminths, and are protected from Ag-induced airway hyperresponsiveness (8, 9).

Th cell differentiation is achieved by chronic stimulation of CD4+ T cells leading to specific patterns of gene expression in the Th1 and Th2 subsets. In this report, we used a PCR-based subtraction method to identify novel genes that are selectively expressed in Th1 cells, which could potentially regulate the function of these cells. We describe the identification of a novel four-transmembrane domain protein, Chandra, that is preferentially expressed in Th1 but not Th2 cells. The expression of Chandra is strictly dependent on the absence of IL-4 signaling in activated T cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice and cell lines

Female BALB/c and AKR/J mice were purchased from Taconic (Germantown, NY). The phenotype of the STAT4- and STAT6-deficient mice have been described previously (6, 7). IFN-{gamma}-deficient mice were purchased from The Jackson Laboratory (Bar Harbor, ME). The phenotype of the STAT1-deficient mice has been previously described (10), and the mice were kindly provided by Dr. Robert D. Schreiber (Washington University School of Medicine, St. Louis, MO). All animals used in this study were between 4 and 6 wk of age. The established Th clones AE7 (Th1) and D10.G4 (Th2) were kindly provided by Dr. Laurie Glimcher (Harvard School of Public Health, Boston, MA). These clones were maintained by biweekly antigenic stimulation with mitomycin C-treated splenocytes from AKR/J mice.

In vitro T cell differentiation

Total splenocytes were differentiated in vitro using a protocol already described (6). Briefly, splenocytes were stimulated for 7 days with plate-bound anti-CD3 (2C11, 2 µg/ml) in the presence of IL-12 (5 ng/ml; R&D Systems, Minneapolis, MN) and anti-IL-4 (11B11, 5 µg/ml; PharMingen, San Diego, CA) for Th1 differentiation and IL-4 (10 ng/ml; Biosource International, Camarillo, CA) and anti-IL-12 (1 µg/ml; R&D Systems) for Th2 differentiation. The cultures were supplemented with recombinant murine IL-2 (10 ng/ml; R&D Systems) on days 2 and 4. All cells were harvested on day 7 and used for further analysis. Enriched CD4+ cells (purity, 75–85%) were prepared by negative selection using CD4+ T cell enrichment columns according to the manufacturer’s instructions (R&D Systems). In experiments involving purified T cells, mitomycin C-treated splenocytes were added in addition to the stimulants described above.

Subtractive hybridization protocol

Th1 and Th2 cells were harvested on day 7, and poly(A)+ RNA was prepared using the FastTrack 2.0 kit (Invitrogen, Carlsbad, CA), according to the manufacturer’s protocol. Subtractive hybridization was performed using a commercial differential PCR-Select Kit (Clontech, Palo Alto, CA). Differential expression of various cDNAs was further confirmed by Northern blot analysis using total RNA prepared from Th1 and Th2 cells. The full-length Chandra cDNA was cloned from a mouse spleen 5'-Stretch Plus cDNA library (Clontech) and later subcloned into the SmaI and XbaI sites of a pRK5 C-terminal flag mammalian expression vector (kindly provided by Dr. H. Wesche, Tularik, South San Francisco, CA).

Northern blot analysis

Total RNA was prepared using Trizol reagent (Life Technologies, Gaithersburg, MD) according to the manufacturer’s instructions. Approximately 10–20 µg of total RNA was subjected to Northern blot analysis using the ExpressHyb hybridization solution (Clontech). The internal primers used to generate the Chandra probe were as follows: sense, 5'-CCCACTTCAGTGATGTTAATGGTC; anti-sense, 5'-CAAATCCTGTTGAGACAGTGATGGC. The same blots were stripped and reprobed for either IL-18R or ß-actin.

Flow cytometry

293HEK cells were transfected using the calcium phosphate method (Promega, Madison, WI) with either the control vector or an expression vector encoding Chandra fused to a C-terminal flag epitope tag. Forty-eight hours posttransfection, cells were stained with anti-flag Ab (Sigma, St. Louis, MO), followed by PE-conjugated anti-mouse secondary Ab (Caltag Laboratories, Burlingame, CA). PE-positive cells were detected by flow cytometry and analyzed using the CellQuest program (Becton Dickinson, San Jose, CA).

Western blot analysis

AE7 and D10.G4 cells (50 x 106 in 1 ml) were incubated with 0.5 mg of sulfo-NHS-LC-Biotin to label cell-surface proteins according to the manufacturer’s protocol (Pierce, Rockford, IL). Cell lysates were incubated with neutravidin beads, and Western blot analysis was performed using a rabbit polyclonal anti-Chandra Ab raised against the C-terminal epitope (aa 206–226) of the protein. For peptide blocking studies, anti-Chandra Ab was incubated with the Chandra-specific peptide (aa 206–226) in a 1:5 (weight) ratio for 2 h at room temperature before incubation with the membrane.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Chandra is differentially expressed in Th1 lymphocytes

To promote Th1 or Th2 differentiation, total splenocytes were stimulated with anti-CD3 and IL-2, along with various combinations of cytokines and anti-cytokine Abs (6). After 7 days of stimulation, total RNA was isolated and Th1- and Th2- specific cDNA pools were prepared. Th1-specific cDNAs were hybridized with excess amounts of Th2-specific cDNAs, and cDNA sequences that were differentially expressed in Th1 cells were selectively amplified using the PCR-based subtraction method. One novel gene, designated Chandra, was selected for further characterization. Chandra mRNA was found in splenocytes activated under Th1 differentiation conditions (Fig. 1GoA). Lower levels of Chandra transcripts were also detected in unactivated splenocytes (Fig. 1GoA, lane 1). The kinetics of Chandra mRNA expression was also studied during Th1 and Th2 differentiation conditions. As shown in Fig. 1GoB, maximal Chandra transcription was observed after 3 days of Th1 differentiation. In contrast, the basal levels of Chandra expression was rapidly down-regulated in developing Th2 cells.



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  		FIGURE 1. Chandra is a Th1-specific gene. A, Total splenocytes from BALB/c mice were left unstimulated (lane 1) or stimulated for 7 days with anti-CD3 and IL-12 plus anti-IL-4 (Th1 conditions, lane 2) or IL-4 plus anti-IL-12 (Th2 conditions, lane 3). Total RNA was prepared and Northern blot analysis was performed using a Chandra-specific probe. The same blot was stripped and reprobed for ß-actin. B, Total splenocytes from BALB/c mice were stimulated under Th1 or Th2 conditions for indicated time periods. Northern blot analysis was performed as described above. C, Enriched CD4+ T cells from BALB/c mice were stimulated for 7 days under neutral (none, lane 1), Th1 (lane 2), or Th2 (lane 3) differentiation conditions. Total RNA was prepared and Northern blot analysis was performed as described above. D, Expression of Chandra in a Th1 cell line. Total RNA prepared from AE7 (Th1) or D10.G4 (Th2) cells was subjected to Northern blot analysis as described above. E, Cell-surface biotinylation was performed on AE7 and D10.G4 cells as described in Materials and Methods. Western blot analysis was performed using polyclonal anti-Chandra Ab.

 
To confirm the differential expression of Chandra in Th subsets, enriched CD4+ cells were activated under Th1 or Th2 conditions. Chandra transcripts were observed only in Th1 cells but not in T cells activated with anti-CD3 plus IL-2 alone (Fig. 1GoC, lanes 1 and 2). As expected, IL-18R transcripts were also seen in Th1 cells (Fig. 1GoC, middle panel). Further, Chandra was differentially expressed in an estabished Th1 (AE7) but not Th2 (D10.G4) clone (Fig. 1GoD). Western blot analysis of cell-surface-labeled proteins also demonstrated that Chandra protein could only be detected in AE7 but not in D10.G4 cells (Fig. 1GoE). These observations established Chandra as a Th1-specific gene.

Chandra is a four-transmembrane domain protein expressed on the cell surface

The open reading frame of Chandra encoded a protein of 226 aa residues with four potential membrane-spanning regions (Fig. 2GoA). To determine whether Chandra was a cell-surface molecule, we constructed a mammalian expression vector encoding Chandra fused to a C-terminal flag epitope tag. Transient transfection experiments using 293HEK cells demonstrated the cell-surface expression of Chandra (Fig. 2GoB). The presence of Chandra protein was verified by Western blot analysis (Fig. 2GoB, bottom panel). These experiments indicated that Chandra was a cell-surface protein with the C terminus of the protein exposed on the exterior surface of the cell.



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  		FIGURE 2. Chandra is a four-transmembrane domain protein expressed on the cell surface. A, Amino acid sequence of full-length Chandra. The four potential transmembrane regions (TM) are underlined. Numbers on the right refer to amino acid residues. B, Chandra is expressed on the cell surface. 293HEK cells were transfected with empty vector (control) or an expression plasmid encoding Chandra fused to a C-terminal flag epitope tag. Cells were stained with anti-flag Abs followed by PE-conjugated anti-mouse secondary Ab. The mean fluorescence intensity is indicated on the x-axis. The bottom panel represents a Western blot analysis of total cell lysates probed with anti-flag Abs. Cells had been transfected as described in the Materials and Methods.

 
Expression of Chandra in Th1 lymphocytes does not require STAT4- or STAT1-dependent signaling pathways

Several studies have shown that IL-12-dependent STAT4 activation is important for the generation of Th1 cells (7). Therefore, we examined whether Chandra expression in Th1 cells required STAT4 signaling events. Similar to wild-type CD4+ T cells, Chandra mRNA was observed in STAT4-deficient Th1 cells (Fig. 3GoA).



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  		FIGURE 3. Chandra expression in Th1 cells is STAT4 independent and does not require IFN-{gamma} signaling. A, Expression of Chandra in Th1 cells is STAT4 independent. Enriched CD4+ T cells from STAT4-deficient mice were stimulated for 7 days under neutral (none, lane 1), Th1 (lane 2), or Th2 (lane 3) differentiation conditions. Total RNA was prepared and Northern blot analysis was performed as described above. B, Chandra is not an IFN-{gamma}-responsive gene. Total splenocytes from IFN-{gamma}-deficient mice were left unstimulated (lane 1) or stimulated for 7 days with anti-CD3 and IL-12 plus anti-IL-4 (lane 2) or IL-4 plus anti-IL-12 (lane 3). Total RNA was prepared and Northern blot analysis was performed as described above.

 
To test whether Chandra was an IFN-{gamma}-responsive gene, total splenocytes from IFN-{gamma}-deficient mice were activated under different conditions. Low amounts of Chandra transcripts were found in unstimulated IFN-{gamma}-deficient splenocytes similar to wild-type splenocytes (Figs. 3GoB and 1A, lane 1). Following activation of splenocytes with anti-CD3 and IL-12 plus anti-IL-4, a significant increase of Chandra mRNA was observed (Fig. 3GoB, lane 2). Costimulation of splenocytes with anti-CD3, IL-4, and neutralizing anti-IL-12 Abs greatly reduced Chandra expression. Similar observations were made when CD4+ T cells from STAT1-deficient mice were differentiated under Th1 or Th2 conditions (data not shown). Taken together, these data clearly showed that Chandra is not an IFN-{gamma}-responsive gene, and its expression in Th1 lymphocytes is independent of STAT4 or STAT1 signaling.

Expression of Chandra is repressed by IL-4 via a STAT6-dependent signaling pathway

STAT6 activation plays a crucial role in the development of Th2 cells (5, 6). Because Chandra transcripts were not detected in Th2 cells, we examined whether IL-4-induced signal transduction could negatively influence Chandra expression by performing experiments with STAT6-deficient CD4+ T cells. Chandra mRNA was readily detected in STAT6-deficient Th1 cells (Fig. 4GoA). Chandra transcripts were also observed when T cells were activated with anti-CD3 in the presence of IL-4 and anti-IL-12 (Fig. 4GoA, lane 3). These results were not surprising because STAT6-deficient mice are severely defective in generating Th2 cells (6). Surprisingly, Chandra transcripts were also detected in anti-CD3-activated T cells (Fig. 4GoA, lane 1). These results provided evidence that Chandra expression in undifferentiated T cells and Th2 cells could be negatively regulated via STAT6-dependent signaling events.



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  		FIGURE 4. Expression of Chandra is repressed by a STAT6-dependent pathway. A, Enriched CD4+ T cells from STAT6-deficient mice were stimulated for 7 days under neutral (none), Th1, or Th2 differentiation conditions. Total RNA was prepared, and Northern blot analysis was performed as described above. B, Enriched CD4+ T cells from wild-type mice were stimulated for 7 days with anti-CD3 in the presence of either 50 µg/ml isotype control IgG or 50 µg/ml neutralizing anti-IL-4 Ab. Total RNA was prepared, and Northern blot analysis was performed as described above. C, Enriched CD4+ T cells from wild-type or STAT6-deficient mice were stimulated for 5 days with anti-CD3 and indicated stimuli in the presence or absence of 20 µg/ml neutralizing anti-IL-12 Ab. Total RNA was prepared, and Northern blot analysis was performed as described above. D, Enriched CD4+ T cells from wild-type mice were stimulated under Th1 differentiation conditions. After 4 days of stimulation, cells were extensively washed and cultured in the presence of IL-4 for 24 or 48 h. Total RNA was prepared, and Northern blot analysis was performed as described above.

 
To test if IL-4 signaling directly inhibits Chandra expression, CD4+ T cells from wild-type mice were incubated with anti-CD3 in the presence of neutralizing anti-IL-4 Ab. Addition of anti-IL-4 but not control IgG was sufficient to induce Chandra transcripts in anti-CD3-activated T cells (Fig. 4GoB). Further, addition of neutralizing anti-IL-12 Ab did not reduce the amount of Chandra transcripts under these conditions in both wild-type and STAT6-deficient mice (Fig. 4GoC), demonstrating that Chandra expression in activated T cells is independent of the IL-12-signaling pathway.

We next examined whether IL-4 signaling can directly repress Chandra transcription in developing Th1 cells. Purified CD4+ T cells were stimulated under Th1 differentiation conditions for 4 days. Subsequently, T cells were cultured with IL-4 for 24 or 48 h, respectively. As shown in Fig. 4GoD, short-term IL-4 treatment did not inhibit Chandra expression in Th1 cells. These results suggested that repression of Chandra by IL-4 signaling is not directly mediated by STAT6.

Collectively, our results demonstrate that Chandra is a novel marker for Th1 cells, and its expression in activated T cells strictly requires neutralization of IL-4 signaling, which is usually seen during Th1 differentiation. The exact mechanism by which STAT6 represses Chandra expression in activated T cells and Th2 cells needs to be determined. Short-term IL-4 treatment does not inhibit Chandra expression in developing Th1 cells, suggesting that STAT6 signaling may induce a repressor protein that blocks Chandra expression in activated T cells and Th2 cells.

Chandra belongs to a family of four-transmembrane domain proteins, which usually form molecular associations with other cell-surface molecules including various integrins (11). A well-characterized member of this family is CD81, which is expressed on T and B lymphocytes. In T cells, anti-CD81 Abs inhibit T cell proliferation and IL-2 production (12). Furthermore, CD81-deficient mice have a defect in IL-4 production and delayed Ab production to T cell-dependent Ags such as OVA or keyhole limpet hemocyanin in alum (13). Other four-transmembrane domain proteins such as CD9, CD53, and CD63 associate with {alpha}3ß1 integrin, regulate cell motility, and induce cell aggregation (11). However, the exact roles of four-transmembrane domain proteins in regulating Th1 and Th2 immune responses have not been examined so far. It is possible that, similar to other members of the four-transmembrane domain proteins, Chandra could also associate with various integrins and promote homotypic cell adhesion or preferential migration of Th1 cells during an immune response. To what extent Chandra favors the commitment of Th cells to a Th1 phenotype remains to be tested using genetic studies.


   Acknowledgments
 
We are thankful to Monique Kuhn and Dong Lee for their excellent technical support and Dr. Tim Hoey for providing useful suggestions and critical comments for this study.


   Footnotes
 
1 Address correspondence and reprint requests to Dr. Ulrike Schindler, Two Corporate Drive, South San Francisco, CA 94080. Back

Received for publication February 9, 2000. Accepted for publication May 19, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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