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The Journal of Immunology, 2002, 169: 5382-5386.
Copyright © 2002 by The American Association of Immunologists

Cutting Edge

Cutting Edge: CD94/NKG2 Is Expressed on Th1 But Not Th2 Cells and Costimulates Th1 Effector Functions1

Jennifer Hartt Meyers*, Akemi Ryu*, Laurent Monney*, Khuong Nguyen*, Edward A. Greenfield2, Gordon J. Freeman and Vijay K. Kuchroo3,*

* Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and {dagger} Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Th1 and Th2 cells can be phenotypically distinguished by very few cell surface markers. To identify cell surface molecules that are specifically expressed on Th1 cells, we have generated a panel of mAbs that specifically bind the surfaces of murine Th1 but not Th2 cells. One of these Abs identified the NK cell receptor CD94 as a molecule also specifically expressed on the surface of Th1 cells. As in NK cells, CD94 is expressed on Th1 cells together with members of the NKG2 family of molecules, including NKG2A, C, and E. Cross-linking these receptors on differentiated Th1 cells in vitro costimulates proliferation and cytokine production with a potency similar to that obtained by cross-linking CD28. We propose that CD94/NKG2 heterodimers may costimulate effector functions of differentiated Th1 cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Activated CD4+ Th cells can be functionally divided into two major subsets, Th1 and Th2. First defined in 1986 (1), these subsets are generally distinguished by their actions, including their production of specific cytokines and involvement in different types of immune reactions. Th1 cells produce IFN-{gamma}, IL-2, TNF, and lymphotoxin and participate in cell-mediated responses to intracellular pathogens, whereas Th2 cells produce IL-4, IL-5, IL-9, IL-10, and IL-13 and are involved in responses to large extracellular pathogens such as helminths (2, 3). The cytokines that drive helper T cell differentiation (IL-12 for Th1 and IL-4 for Th2) have been well characterized, but exactly how differentiation occurs is just beginning to be understood. In addition, a detailed surface phenotype of either subset that could unambiguously distinguish it from the other has not been defined (4). Although specific chemokine receptors are preferentially expressed on different subsets of lymphocytes, these differences are largely quantitative (4). The first steps have been taken toward the description of unique surface phenotypes for these cells by the identification of T1/ST2 as a stable marker for Th2 cells (5) and Tim-3 as a Th1 marker (6). We have chosen to seek additional Th1-specific molecules, because these would play a role in Th1 activation, differentiation, and/or effector function. They would therefore be useful not only for the detection of Th1 cells during an immune response but also for analysis of their functions.

To more clearly define the molecules that are selectively expressed on the surface of Th1 cells, we have generated a panel of mAbs that selectively recognize Th1 cells and have taken an expression cloning approach to the identification of their targets. Here we identify the NK cell receptor CD94 (7) as a molecule expressed on differentiated Th1 cells but not on Th2 cells. This receptor is coexpressed, as it is in NK cells, with the NKG2 family of proteins, and the entire array of CD94/NKG2 receptors (both activating and inhibitory varieties) appears to be expressed in Th1 cells. Preliminary functional assays suggest that these NK receptors could costimulate the expansion and cytokine production of differentiated Th1 cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Cells and Abs

The AE7, D10G4, and 7A5 clones and DO11.10 transgenic mice have been previously used in our publications (6). The 2D2 Th1 clone is specific for MOG35–55/IAb, and Q1.4A11 and Q1.3C11 are Th2 clones specific for an altered peptide of PLP139–151, Q144, recognized in the context of IAs (all generated in our laboratory).

Abs to CD94 (18d3) and NKG2A/C/E (20d5), as well as Abs to IFN-{gamma} (XMG1.2), IL-10 (JES5-16E3), IL-4 (11B11), CD4 (GK1.5), CD62L (MEL-14), and CD44 (IM7), and streptavidin-PE were from BD Phar-Mingen (San Diego, CA). FITC- and PE-labeled goat anti-rat IgG Abs were from Caltag Laboratories (Burlingame, CA).

In vitro T cell polarization

For the generation of DO11.10 Th1 and Th2 cells, CD62LhighCD44low-sorted naive DO11.10 transgenic T cells were stimulated in vitro for 7 days with OVA323–339 peptide (10 µg/ml; Quality Controlled Biochemicals, Hopkington, MA) and irradiated BALB/cJ splenocytes under polarizing conditions (Th1, 5 ng/ml mIL-12 (BD PharMingen) and 10 µg/ml anti-mIL-4; Th2, 10 ng/ml mIL-4 (R&D Systems, Minneapolis, MN) and 10 µg/ml anti-mIL-12 (BD PharMingen)). Cells were subjected to four rounds of polarization and were stained for intracellular cytokine production as described previously (6) and for surface staining with 18D1 on day 10 after each round.

Generation of Th1-specific mAb

Female Lewis and Lou/m rats (Harlan Sprague Dawley; Harlan Breeders, Indianapolis, IN) were immunized three times with s.c. injections of 1 or 5 x 107 Th1-polarized T cell clones and/or lines. Spleen cells from these rats were fused with myeloma cells, and supernatants thus obtained were screened by flow cytometry on Th1 and Th2 cells. Selected hybridomas that stained all Th1 but no Th2 cells were subcloned.

Expression cloning

A eukaryotic expression library was constructed using mRNA from the AE7 Th1 clone and the pAXEF vector. Library screening was performed through expression cloning as previously described (8). Immunoselected individual plasmids were transiently transfected into COS cells followed by indirect immunofluorescence staining with the 18D1 mAb. Positive clones were sequenced. From one of these positive clones, a stable CD94 transfectant was made in HEK 293 cells using pcDNA3.1- (Invitrogen, San Diego, CA) with 1 mg/ml G-418 (Life Technologies) as the selective agent.

RT-PCR

RNA was prepared from 106 cells using the Trizol reagent (Life Technologies, Gaithersburg, MD), followed by cDNA synthesis by the SuperScript protocol (Life Technologies). CD94 was amplified from the cDNA using the primers mCD94-Xho-Koz and mCD94-3'HA-Bam (7). Primers used for specific amplification of NKG2 family members are NKG2A5, NKG2A3 (9), NKG2C5, NKG2C/E3 (10), NKG2E5 (11), NKG2D5, and NKG2D3 (12). Thirty-five cycles of PCR were performed, using 2 µl cDNA under the following conditions: 94°C for 2 min (94°C for 45 s, 60°C for 45 s (53°C for the actin primers), 72°C for 75 s) for 35 cycles; 72°C for 10 min.

Proliferation and cytokine ELISAs

Latex beads (5.2 µm in diameter; Interfacial Dynamics, Portland, OR) were incubated at 107/ml in PBS with anti-CD3 (0.5 or 0.25 µg/ml) at 37°C for 30 min and then centrifuged at 3500 rpm for 15 min. The beads were then incubated as above with anti-CD94, anti-CD28, anti-NKG2A/C/E, and/or rIgG at 4, 2, 1, and 0.5 µg/ml (rIgG was used to adjust the total amount of protein in each reaction to equal that in the anti-CD94 plus anti-NKG2A/C/E sample). Beads were washed, resuspended in clone medium, and added to round-bottom 96-well plates at 105 or 5 x 104 beads/well. DO11.10 Th1 cells were then plated at 5 x 105 cells/well. After 48 h, supernatants were removed for cytokine analysis, and plates were pulsed with 1 µCi [3H]thymidine per well for 16 h. The incorporated thymidine was measured with a beta plate scintillation counter (PerkinElmer Wallac, Gaithersburg, MD). Cytokine analysis was performed by quantitative capture ELISA (BD PharMingen). Assays were developed with TMB Microwell Peroxidase Substrate (Kirkegaard & Perry Laboratories, Gaithersburg, MD) and read at 450 nm.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Generation and characterization of a mAb to a Th1-specific cell surface molecule

To generate Abs specific to the surface of Th1 cells, we immunized Lewis and Lou/M rats with the established murine T cell clone AE7 and a Th1 cell line derived from DO11.10 TCR-transgenic mice. A panel of ~20,000 mAbs was thus produced and screened on polarized Th1 and Th2 T cell clones and cell lines. One of these mAbs, named 18D1, selectively recognized a molecule common to all four Th1 cells tested but did not bind any Th2 cells (Fig. 1GoA).



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  		FIGURE 1. 18D1 mAb recognizes a surface molecule present on Th1 but not Th2 cells. A, T cell clones/lines were stained with 18D1 hybridoma supernatants (solid histograms) or rat IgG (open histograms) and with polyclonal goat anti-rat-FITC. At least 10,000 cells/sample were analyzed by flow cytometry. Histograms depict cell number vs relative log10 fluorescence. B, Naive DO11.10 T cells were stimulated in vitro under Th1- or Th2-polarizing conditions. After each round of restimulation, Th1 and Th2 cells were stimulated with PMA-ionomycin for the induction of cytokines and then stained with 18D1 and anti-CD4, and cytokine expression was detected by intracellular staining as previously described (6 ). Histograms represent 18D1 staining on CD4+ cells (·····, isotype control; , specific staining). Dot plots (logarithmic scale) represent cytokine expression in CD4+ cells.

 
To determine the expression pattern of the molecule recognized by the 18D1 mAb during Th cell differentiation, we isolated naive CD4+ T cells from DO11.10-transgenic mice and activated them in vitro under polarizing conditions to induce their differentiation into either the Th1 or Th2 subset. As shown in Fig. 1GoB, staining by 18D1 mAb was absent on naive helper T cells but appeared on Th1 cells by the third round of polarization and did not appear on Th2 cells through four rounds of polarization. These data suggest that the molecule recognized by 18D1 is expressed selectively on differentiated Th1 cells and not on naive T or differentiated Th2 cells.

Expression cloning of CD94 as a molecule expressed on Th1 cells

Expression cloning using the 18D1 mAb and a cDNA library from Th1 clone AE7 selected clones containing a single, ~500 bp cDNA, which we found encoded full length CD94. We confirmed the identification of 18D1 as anti-CD94 by transiently transfecting COS cells with the CD94 cDNA and demonstrating that both 18D1 and previously characterized anti-CD94 mAb 18d3 stained the transfectants but not untransfected cells (data not shown). We also stably transfected the CD94 cDNA into HEK 293 cells and saw the same staining pattern as with the transient transfectant (Fig. 2GoA). In addition, both anti-CD94 mAb 18d3 and 18D1 stained our panel of differentiated Th1 cells but not the Th2 cells (Fig. 2GoB and data not shown). Thus, it would appear that full length CD94 is present on the surface of differentiated mouse Th1 cells but not on that of Th2 cells.



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  		FIGURE 2. A, 18D1 mAb recognizes CD94. HEK 293 cells stably transfected with CD94 cDNA in pcDNA3.1 were stained with 18D1, biotinylated anti-CD94 mAb 18d3, or isotype control. Staining was detected with polyclonal goat anti-rat FITC (18D1) or streptavidin-PE (CD94). Solid histograms, specific staining; open histograms, untransfected HEK 293 cells stained with specific Abs. B, CD94 is expressed with NKG2 family members on Th1 cells. T cell clones were stained with 18D1 mAb together with either biotinylated anti-CD94 (18d3) or biotinylated anti-NKG2A/C/E (20d5). Staining was detected as in A.

 
Coexpression of CD94 with NKG2 family members on Th1 cells

Because CD94 has been demonstrated to be expressed only in dimeric form (13), we next assessed whether it was expressed on Th1 cells with its usual partners, the NKG2 molecules. Flow cytometric analysis of Th1 cells revealed that these cells expressed both CD94 and NKG2 molecules, whereas Th2 cells consistently expressed neither molecule (Fig. 2GoB and data not shown).

The only commercially available mouse anti-NKG2 Ab recognizes both the inhibitory (NKG2A (14)) and activating (NKG2C and NKG2E (11)) members of the NKG2 family; therefore, we could not by Ab staining determine which NKG2 molecules were present on the cells studied. We therefore used primers specific for the individual members of the family to examine expression in two different pairs of differentiated Th1 and Th2 cells by RT-PCR. Fig. 3Go shows that NKG2A, -C, and -E all appear to be expressed specifically in Th1 cells, whereas NKG2D, which does not pair with CD94 (15), is expressed in both Th1 and Th2 cells. Several splice variants of NKG2C have been reported (16); therefore, the multiple cDNA species observed in the NKG2C lane are not unexpected. The higher molecular mass band seen in the D10G4 NKG2A lane was not consistently observed but could potentially be NKG2B (which is an alternately spliced form of NKG2A) (13). Thus, the full complement of NKG2 family members is present, at least at the mRNA level, in these cells.



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  		FIGURE 3. CD94 and NKG2 molecules are preferentially expressed on Th1 cells. mRNA was prepared from T cell clones (AE7 = Th1, D10G4 = Th2) or polarized Th1 and Th2 lines derived from DO11.10 TCR transgenic mice, and 35 cycles of RT-PCR were performed using specific primers for CD94, NKG2A, NKG2C, NKG2D, NKG2E, and actin.

 
CD94/NKG2 receptors costimulate proliferation and cytokine production of Th1 cells

The observation that CD94/NKG2 dimers are specifically expressed on differentiated Th1 cells suggests that these molecules might play a role in Th1 cell effector function. To address this possibility, we tested the effects of cross-linking CD94 and NKG2 molecules on in vitro Th1 cell activation. Latex beads coated with anti-CD3, anti-CD94, and anti-NKG2A/C/E were used to activate Th1 cell lines. Co-cross-linking of CD3 and CD94/NKG2 receptors on the surfaces of DO11.10-polarized Th1 but not Th2 cells resulted in a marked increase in proliferation and production of IFN-{gamma} and TNF-{alpha} over that induced by anti-CD3 stimulation alone (Fig. 4GoA and data not shown). To address whether this costimulatory effect was due to cross-linking of CD94, NKG2, or both, we coated beads with anti-CD3 plus either anti-CD94 or anti-NKG2A/C/E. In these experiments, beads coated with anti-CD3 plus rat IgG were used as a negative control and anti-CD3 plus anti-CD28 was used as a positive control. When DO11.10 polarized Th1 cells were stimulated with these beads in vitro, anti-CD3 plus anti-CD94 cross-linking led to a small but definite increase in proliferation and cytokine production over the anti-CD3 plus rIgG control, and anti-CD3 plus anti-NKG2A/C/E stimulation by the mAbs led to marked increases in proliferation (Fig. 4GoB). The co-cross-linking by all three mAb (anti-CD3 plus anti-CD94 plus anti-NKG2)-bearing beads resulted in additional activation in terms of proliferation and cytokine production over anti-CD3 plus anti-NKG2 cross-linking, with a particularly large increase in IFN-{gamma} production. In some experiments, however, we saw very little difference between cross-linking of CD3 plus CD94 plus NKG2 and that of CD3 plus NKG2, although both induced a significant increase in proliferation and IFN-{gamma} production over anti-CD3 plus rIgG treatment. Surprisingly, the activation induced by cross-linking of CD3 plus CD94 plus NKG2 on Th1 cells was similar to that observed with cross-linking of CD3 plus CD28 on these cells. These data suggest that CD94/NKG2 dimers expressed on differentiated Th1 cells can costimulate Th1 cell effector functions.



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  		FIGURE 4. CD94/NKG2 costimulate Th1 expansion and cytokine production. A, DO11.10 Th1 cells (5 x 105/well) were incubated with 105 (cytokine plots) or 5 x 104 (proliferation plot) latex beads coated with 0.5 µg/ml anti-CD3 and either rIgG or anti-CD94 (18d3) and anti-NKG2A/C/E (20d5). After 48 h, culture supernatants were removed for cytokine analysis by ELISA, and cells were pulsed with 1 µCi [3H]thymidine/well for 16 h. Ab concentrations shown on the x-axis are of anti-CD94, anti-NKG2, or one-half of total rIgG concentration. B, DO11.10 Th1 cells were incubated as above with 105 beads/well coated with 0.25 µg/ml anti-CD3 together with various concentrations of other Abs as shown in the legend. Similarly to A, the x-axis value is the concentration of anti-CD94, anti-NKG2, anti-CD28, or rIgG. An equal amount of rIgG was added to each sample except the anti-CD94- plus anti-NKG2-coated beads. Cytokines were analyzed by ELISA, and proliferation was measured by [3H]thymidine incorporation.

 
CD94 and its partners have been observed on the surfaces of several types of non-NK cells, including NK1.1+ T cells, {gamma}{delta} T cells, and CD8+ T cells (17, 18), but to our knowledge they have not been reported on polarized CD4+ T cells. The vast majority of CD4+ T cells indeed do not express this receptor, because effector Th1 cells make up a very small percentage of the total CD4+ T cell population, although some human CD4+ T cells have been shown to express CD94 when manipulated in vitro (19). As our data show, CD94/NKG2 is absent from naive T cells and is seen on Th1 cells only after three rounds of activation and polarization. This rationale likely explains why CD94/NKG2 expression on Th1 cells was not detected in previous studies of CD4+ T cells.

Although CD94/NKG2 has not been directly observed on Th1 cells, functional experiments suggesting such expression have recently accumulated. Data on the effects of a deficiency in DAP12, the ITAM-containing molecule through which the activating signals of CD94/NKG2C/E receptors are transduced (20), strongly suggest a role for these receptors in Th1 function. Bakker et al. (21) found that their DAP12 knockout mouse produced lower levels of IFN-{gamma} on Ag-specific activation and was resistant to induction of the Th1-mediated disease experimental autoimmune encephalomyelitis. In light of the present data, it seems likely that these mice avoided autoimmunity by losing the ability to fully induce the effector functions of their Th1 cells. Additionally, Nickoloff et al. (22) found that CD4+ T cells expressing CD94/NKG2 and other NK cell receptors could induce psoriatic plaques upon injection into human skin grafted onto SCID mice, suggesting that autopathogenic CD4+ T cells can express CD94/NKG2 receptors.

The data presented in this paper clearly demonstrate that CD94/NKG2 receptors are expressed on Th1 cells, and cross-linking these receptors together with CD3/TCR costimulates proliferation and cytokine production from Th1 cells. In addition, CD94/NKG2 molecules could be involved, as in NK cells and CD8+ T cells (13, 17, 23), in modulating the cytotoxic functions of Th1 cells. CD28 costimulation has been shown to be required not only for the activation and expansion of naive T cells but also for their effector functions and survival (24). As not all tissues express B7 molecules, it is possible that CD94/NKG2 could evoke effector functions and prevent Th1 cell anergy in tissues that lack B7. This possibility is supported by data showing that CD94/NKG2 expression appears on T cells as CD28 is down-regulated during activation (25). However, whether CD94/NKG2 receptors costimulate a positive signal or dampen a negative signal remains to be seen. Although these Th1 cells express the inhibitory molecule NKG2A as well as stimulatory NKG2 molecules (Fig. 3Go), it is possible that the cumulative activation of the TCR and stimulatory CD94/NKG2C/E receptors could override this potential inhibition.

In summary, CD94/NKG2 receptors, which were originally thought to be important specifically to NK cell function, are also expressed on differentiated Th1 cells and may play an important role in costimulating and tuning their effector functions.


   Acknowledgments
 
We thank Robert McGilp for expert cell sorting and Estelle Bettelli and Lindsay B. Nicholson for providing the 2D2 and Q1.3C11 clones.


   Footnotes
 
1 This work was supported by National Institutes of Health Grants R01NS30843, R01NS35685, P01AI39671-01A1, and PO1NS38037-01A1 and National Multiple Sclerosis Society Grant (RG2571) (to V.K.K.). J.H.M. is a predoctoral fellow of the Howard Hughes Medical Institute. Back

2 Current address: Millennium Pharmaceuticals, Cambridge, MA 02139. Back

3 Address correspondence and reprint requests to Dr. Vijay K. Kuchroo, Center for Neurologic Diseases, 77 Avenue Louis Pasteur, HIM/Room 710, Boston, MA 02115. E-mail address: vkuchroo{at}rics.bwh.harvard.edu Back

Received for publication August 19, 2002. Accepted for publication September 20, 2002.


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 Materials and Methods
 Results and Discussion
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*HomoloGene*UniGene
*Substance via MeSH

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