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The Journal of Immunology, 2005, 174: 4480-4484.
Copyright © 2005 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: NKG2D Is a Costimulatory Receptor for Human Naive CD8+ T Cells

Kerima Maasho, Jessica Opoku-Anane, Alina I. Marusina, John E. Coligan and Francisco Borrego1

Receptor Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
In humans, all {alpha}{beta} CD8+ T cells express NKG2D, but in mouse, it is only expressed by activated and memory CD8+ T cells. We purified human naive CD8+ T cells to show that NKG2D serves as a costimulatory receptor for TCR induced Ca2+ mobilization and proliferation. The resulting effector cells are skewed toward a type 1 phenotype and produce high levels of IFN-{gamma} and TNF-{alpha}. NKG2D ligands, MHC class I chain-related (MIC)A, MICB, and UL16-binding proteins are expressed on the proliferating cells and NKG2D is down-regulated. The addition of the homeostatic cytokines IL-7 and IL-15 to the culture medium not only enhances proliferation but also counteracts the down-regulation of NKG2D, more so than the addition of IL-2. These results indicate that NKG2D can regulate the priming of human naive CD8+ T cells, which may provide an alternative mechanism for potentiating and channeling the immune response.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
The fate of naive T cells is affected by the conditions under which they encounter the Ag. Successful clonal expansion of naive T cells after interaction with APCs is determined by Ag dose, duration of the signal, and costimulation (1). The latter is effected through the interaction of co-receptors on the surface of T cells with their ligands on APCs (2, 3) or by soluble factors, such as cytokines and chemokines (4). After encountering Ag, naive T cells adopt one of the two distinct effector cell fates. Type 1 cells (Th1/Tc1) are characterized by the production of IFN-{gamma}, TNF-{alpha}, and IL-2, whereas type 2 cells (Th2/Tc2) produce IL-4, IL-5, IL-10, and IL-13 (5).

NKG2D is expressed on almost all NK cells, CD8+ T cells, and {gamma}{delta} T cells (6). Whereas only activated and memory mouse CD8+ T cells express NKG2D, all human CD8+ T cells express this receptor (6). NKG2D has no intrinsic signaling capacity, but attains this by association with the transmembrane signaling adaptor protein DAP10 (7). Several studies have shown that NKG2D is a primary activation receptor on NK cells, meaning that engagement of NKG2D alone is enough for the transmission of a signal that results in NK cell-mediated cytotoxicity (8). In contrast, several studies made with T cell clones and activated T cell lines have shown that NKG2D serves as a costimulatory receptor for TCR-mediated signals in a manner similar to CD28 (8, 9).

Multiple ligands have been described for human NKG2D, including MHC class I chain-related (MIC)A,2 MICB, and UL16-binding proteins (ULBP) (6, 10, 11). MICA and MICB are normally expressed only by intestinal epithelial cells (12). Tumor cell lines and primary tumors of epithelial origin express MICA and MICB (13). The expression of NKG2D ligands is also up-regulated in cells infected with certain pathogens (9, 14). In addition, NKG2D and NKG2D ligands also appear to play a role in the pathogenesis of diseases that are associated with type 1 (Th1/Tc1) T cell-dependent responses against autoantigens, such as diabetes in the NOD mouse (15), and celiac disease (16, 17) and rheumatoid arthritis in humans (18). Finally, and perhaps of great significance for the regulation of the immune response, IFN-{alpha} activated dendritic cells (DC) have been shown to express MICA and MICB (19).

Because the priming of naive T cells dictates the nature of the effector and memory T cell populations, we examined whether NKG2D costimulation could channel the development of these populations. Our results show that NKG2D is a costimulatory molecule for TCR-mediated signals in naive CD8+ T cells and that the engagement of NKG2D along with the TCR favors the development of Tc1 over Tc2 cells. In addition, we have found that after stimulation, CD8+ T cells express ligands for NKG2D, which presumably accounts for the observed down-regulation of NKG2D by activated human CD8+ T cells. This down-regulation is suppressed by the presence of the homeostatic cytokines IL-7 and IL-15.


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

Allophycocyanin-conjugated anti-CD62L (BD Biosciences) and FITC-conjugated anti-CD45RO (eBiosciences) were used in three-color FACS analysis and for cell sorting. PE-conjugated anti-CD11a, CD25, CD27, CD28, CD62L, CD94, NKG2A (Beckman Coulter), CCR7, NKG2D (R&D Systems), CD45RA, CD45RO, CCR4 and LAIR-1 (BD Biosciences) were used for phenotypic analyses. Purified anti-CD3 mAb (clone UCH1, mouse IgG1; Beckman Coulter) and anti-NKG2D (clone 149810, mouse IgG1; R&D Systems) were used for cell stimulation. Anti-MICA mAb (Immatics Biotechnologies) and PE-conjugated goat anti-mouse (GAM) IgG (Beckman Coulter) were used in the indirect immunofluorescence assay. GAM IgG (Jackson ImmunoResearch Laboratories) was used for cross-linking of the primary Abs in the Ca2+ flux assay.

Cell isolation and sorting

Human CD8+ T cells were isolated from buffy coat by negative selection using a CD8+ T cell isolation kit (Miltenyi Biotec). Naive CD8+ T cell populations, based on CD62L+CD45RO– phenotype, were isolated at the NIAID sorting facility. After sorting, cells were resuspended in T cell medium: IMDM medium (Invitrogen Life Sciences) containing 10% human AB serum (Valley Biomedical) and supplemented with GlutaMAX (Invitrogen Life Sciences) and penicillin/streptomycin (BioSource International).

Ca2+ flux assay

Naive CD8+ T cells were washed and resuspended in HBSS (Invitrogen Life Sciences) with 1% FCS at 5 x 106 cells/ml. Then, cells were labeled with Fluo-4 (2 µg/ml) and Fura Red (5 µg/ml) (Molecular Probes) for 30 min at 30°C. Cells were washed two times and resuspended at 2 x 106 cells/ml. Then, they were incubated in a water bath at 37°C for 5 min, followed by FACS. To establish a baseline, cells were acquired for 30 s, at which point primary mAb were added, and acquisition of cells was continued for 30 s. The primary mAb were cross-linked with GAM IgG. Data were analyzed using the FlowJo 4.2 software package (Treestar).

Cell activation/analysis

Unlabeled or CFSE-labeled naive CD8+ T cells (0.5 x 106 cells in 0.5 ml) were added to 48-well plates coated with anti-CD3 mAb alone at 0.1 µg/ml, or in conjunction with 1 µg/ml of anti-NKG2D mAb. Cells were cultured for different time points and then transferred into noncoated wells. At the time of transfer, 50 U/ml human recombinant IL-2 (NCI-FRDC, Frederick, MD) or 10 ng/ml IL-7 plus 10 ng/ml IL-15 (R&D Systems) were added to each well. To favor Tc2 development, whole or naive CD8+ T cells were cultured with 50 U/ml IL-2, 10 ng/ml IL-4, and 1 µg/ml anti-human IFN-{gamma} mAb (BD Biosciences). Cells were analyzed by flow cytometry at days 4 and 7.

Cytokine analysis

Naive CD8+ T cells stimulated and cultured as above were harvested at day 7, washed and adjusted to 1 x 106 cells/ml in T cell medium. Cells were cultured in wells coated with 0.1 µg/ml anti-CD3 mAb in a recall assay for 24 h at which time supernatants were collected for cytokine analysis. The human Th1/Th2 cytokine cytometric bead array kit (BD Biosciences) was used to quantitatively measure cytokine levels.

RT-PCR analysis

Total RNA was isolated from unstimulated cells at day 0 and anti-CD3 or anti-CD3 + anti-NKG2D-stimulated cells at day 7, using RNeasy Mini kits (Qiagen), and synthesis of cDNA was performed using the SuperScript III first-strand synthesis system for RT-PCR (Invitrogen Life Sciences). The PCR reaction was done using specific pairs of primers to detect MICA, MICB, ULBP-1, -2, and -3. Primer sequences for the NKG2D ligands were ULBP-1 forward, 5'-AGGCCAAAGCCTTTGCTTCT-3', and reverse, 5'-AAATTCTTCAAGCCACATC-3'; ULBP-2 forward, 5'-CAGTCACACCTGTCAGTCC-3', and reverse, 5'-TCCCATTGAGAAGTAATG-3'; ULBP-3 forward, 5'-AGGTCTTATCTATGGGTCAC-3', and reverse, 5'-GGGTTCCAGCCTCTTCTTCCTG-3'. Specific primers for MICB were previously described (19). The housekeeping gene GAPDH was detected with the following primers: forward, 5'-CCGTCTAGAAAAACCTGCC-3', and reverse, 5'-GCCAAATTCGTTGTCATACC-3', primers.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
Three-color analyses showed that the naive CD8+ T cells, identified by the CD62L+CD45RO– phenotype, express slightly lower levels of NKG2D than other CD8+ T cell subsets (Fig. 1A). We then obtained the naive CD8+ T cell population by sorting for the cells that are CD62L+CD45RO–. This naive cell population was further characterized by examining its receptor expression profile, which revealed the following phenotype: CD11alow, CD27+, CD28+, CD45RA+, LAIR-1+, CCR7+ (Fig. 1B), CCR4–, CD25–, CD94–/NKG2A– (data not shown).



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  		FIGURE 1. NKG2D is expressed by all human CD8+ T cells. A, Freshly isolated, CD8+ T cells were labeled with anti-CD62L, anti-CD45RO and anti-NKG2D mAb for 3 color FACS analysis. Subpopulations of the CD8+ T cells were gated according to their CD62L/CD45RO expression profile (dot plot). Each subpopulation was further analyzed for their expression of NKG2D (histograms). Numbers in histograms indicate mean fluorescence intensity (MFI). B, Sorted human naive CD8+ T cells (CD62L+CD45RO–) were analyzed by FACS for expression of cell surface Ags at day 0. Empty histograms represent isotype controls and filled histograms represent the indicated cell surface Ag. Results are representative of 10 donors.

 
Initially, we investigated if NKG2D could function as a co-stimulatory receptor for human naive CD8+ T cells. First, we analyzed for the ability of NKG2D to costimulate TCR signaling. We did this by measuring Ca2+ mobilization in response to receptor cross-linking. This was done immediately after the isolation of the naive CD8+ T cells to overrule any contribution from other receptors and cytokines that might appear during cell culture. We observed that cross-linking of TCR with anti-CD3 mAb induced Ca2+ mobilization within seconds, whereas cross-linking of NKG2D by itself did not induce any response. This indicates that NKG2D cannot act alone to stimulate naive CD8+ T cells. When TCR is engaged along with NKG2D, a dramatic increase in Ca2+ mobilization was observed in comparison to cross-linking TCR alone (Fig. 2A). This clearly indicates that NKG2D acts as a costimulatory receptor for TCR signaling (2, 3). Our preliminary experiments with MICA tetramers have shown them to be as effective as anti-NKG2D mAb in costimulating TCR-induced Ca2+ mobilization in CD8+ T cells (data not shown). Next, we examined the effect of NKG2D cross-linking on CD8+ T cell proliferation. Naive CD8+ T cells were labeled with CFSE and stimulated with immobilized anti-CD3 mAb in the absence or presence of anti-NKG2D mAb. At different time points, the cells were detached and transferred to uncoated wells; then 50 U/ml IL-2 was added to each well. Cells were further cultured up to day 4 or 7. We observed that the extent of proliferation was directly related to the duration and the strength of the stimuli (Fig. 2B). Few cells divide if TCR stimulation is only for 24 h, but more cells divide if there was NKG2D costimulation. More cells are dividing after 48 and 72 h of TCR stimulation than after 24 h, and the number is dramatically enhanced if NKG2D is co-ligated along with the TCR. Phenotypic analyses of the stimulated CFSE-stimulated cells showed that proliferating cells costimulated with NKG2D express higher levels of CD11a, CD45RO, and CD25 than those stimulated with anti-CD3 alone (Fig. 2C). As expected, other typical surface markers for naive cells, such as CD45RA and CD62L, were down-regulated by proliferating cells (data not shown). Expression levels of the CD27 and CD28 receptors were minimally changed, and we did not see a significant increase of CD94/NKG2A expression on the proliferating CD8+ T cells, while the expression of the LAIR-1 inhibitory receptor was increased (data not shown). We obtained equivalent proliferative responses when we used anti-CD28 mAb as costimulatory agent for these cells (data not shown). Taken together, these results indicate that NKG2D is a costimulatory receptor for human naive CD8+ T cells and suggest that its ligation can act to increase the fitness of stimulated T cells.



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  		FIGURE 2. Costimulation of human naive CD8+ T cells by NKG2D. A, Flow cytometric analysis of Fluo-4 and Fura-Red labeled human naive CD8+ T cells are shown. Intracellular Ca++ concentration was measured by the ratio of Fluo-4/Fura Red as a function of time. B, Freshly isolated human naive CD8+ T cells were labeled with CFSE and cultured in vitro with immobilized anti-CD3 mAb or anti-CD3+anti-NKG2D mAb. Cells were further cultured in the presence of IL-2 after transferring from mAb coated wells. Numbers within the panels indicate the percentage of cells in the culture that have entered division. C, CD11a, CD25 and CD45RO expression on stimulated cells. The percentage of cells in each quadrant and the mean fluorescence intensity of the positive proliferating cells is indicated. These results are representative of 5 experiments.

 
CD8+ T cell responses are very important for defense against a variety of intracellular infections, as well as for arresting tumor development (20, 21). On the other hand, they can contribute to the pathogenesis of certain autoimmune diseases (15, 16, 17). Such responses can be mediated through the production of type 1 cytokines, such as IFN-{gamma} and TNF-{alpha}, and/or by cytolytic mechanisms. In this regard, we investigated the functional capacity of TCR-stimulated CD8+ T cells with or without co-stimulation by NKG2D. Cells cultured for 7 days were restimulated with anti-CD3 mAb for 24 h in a recall assay, followed by analyses of the cytokine production profile. Our results show that cells that were primed with anti-CD3 mAb in the presence of NKG2D costimulation tend to produce more type 1 cytokines (IFN-{gamma} and TNF-{alpha}). This, along with a lack of increase in type 2 cytokines (IL-4 and IL-5) (Fig. 3A), suggests that NKG2D is a proinflammatory coreceptor. To further confirm that NKG2D costimulation favors the development of Tc1 vs Tc2 cells, we checked the expression levels of the type 2 cell marker CCR4 (22) by the proliferating cells. TCR or TCR + NKG2D-stimulated whole or naive CD8+ T cells were cultured in the presence of IL-2 or in IL-2 + IL-4 and anti-IFN-{gamma} mAb, in the case of the latter, with the objective of promoting Tc2 development. In cells cultured in type 2 polarizing conditions, we observed that NKG2D costimulation inhibited the up-regulation of CCR4 compared with cells that received only TCR stimulation (Fig. 3B).



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  		FIGURE 3. NKG2D costimulation favors the development of Tc1 cells. A, Freshly isolated naive CD8+ T cells were cultured in vitro under the same conditions as were used to obtain the data reported in Fig. 2b except without CFSE labeling. At day 7, cells were restimulated with anti-CD3 mAb for 24 h and cytokine levels in the culture supernatant were measured. Bars indicate the average and the dots indicate the individual responses. B, Freshly isolated naive CD8+ T cells were stimulated with anti-CD3 mAb or anti-CD3+anti-NKG2D mAb in the presence of IL-2 or IL-2, IL-4 and anti-IFN-{gamma} mAb. After day 3, cells were transferred to noncoated wells and cytokines were added again. The expression of CCR4 was measured at day 11. Results are representative of 3 experiments.

 
When T cells are no longer in contact with Ag, they become susceptible to death by neglect, and to avoid this, they need survival signals mediated by the constitutively expressed homeostatic cytokines IL-7 and IL-15 (4, 23). In contrast, IL-2, which acts in the Ag-driven phase of T cell maturation development, has been postulated to control late clonal expansion by inducing T cell death (4). Consequently, after Ag withdrawal, we compared the effect of IL-2 vs IL-7 plus IL-15 on activated naive CD8+ T cells. Cells that were stimulated with anti-CD3 mAb or anti-CD3 + anti-NKG2D mAb for 72 h were transferred to non-coated wells and cultured with IL-2 or IL-7 + IL-15. As expected, analyses at day 7 showed that NKG2D costimulation in both conditions increases the number of dividing cells, albeit more so in the presence of IL-7 + IL-15 (Fig. 4A). This indicates that NKG2D promotes cell fitness even if only IL-2 is present. We also observed by FACS analyses that there were more cells with a lower forward scatter, suggesting progression toward cell death, if they were grown in the presence of IL-2 alone compared with IL-7 + IL-15 (data not shown).



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  		FIGURE 4. Role of IL-7 and IL-15 in NKG2D mediated costimulation and induction of NKG2D ligands. A, Human naive CD8+ T cells were cultured in vitro as they were in Fig. 2B. Upon transfer of cells to noncoated wells at day 3, IL-2 or IL-7+IL-15 were added to the wells. On day 7, cells were analyzed for CFSE dilution. The percentage of cells that have divided 3 or more times is indicated. B, Percentage of NKG2D positive CD8+ T cells after 7 days of culture with IL-2 or IL-7+IL-15. Results are representative of 5 experiments. C, MICA expression by cultured cells in the presence of IL-7+IL-15 at day 7 as determined by flow cytometric analysis and for MICB, ULBP-1, –2 and –3 by RT-PCR.

 
It has been shown that the ligation of NKG2D induces its down-regulation from the cell surface (13) and that IL-15 can induce the expression of NKG2D (24). We checked NKG2D expression levels and observed that cells that were costimulated by NKG2D maintained higher levels of NKG2D cell surface expression if they were cultured in the presence of IL-7 + IL-15 than if they were cultured with IL-2 alone (Fig. 4B). Finally, we examined NKG2D ligand expression levels on proliferating cells. In accordance with the literature (25), we observed that MICA was induced upon activation of CD8+ T cells. MICA expression was not significantly enhanced by NKG2D costimulation compared with anti-CD3 stimulation alone. We also observed an increase in the message levels of ULBP-1, -2, and -3 (Fig. 4C). Thus, our results show that the homeostatic cytokines IL-7 and IL-15 increase the proliferative response of naive CD8+ T cells and suggest that this may be due to the prevention of the anticipated ligand-induced down-regulation of NKG2D.

The duration and strength of the Ag-induced signal, as well as the presence of costimulation, has a direct impact on the ability of the cells to attain fitness, which is defined by the capacity to respond to homeostatic cytokines and to resist death by neglect (23). Our results show that NKG2D costimulated human naive CD8+ T cells are functionally more fit, because they respond better to homeostatic cytokines, than cells that have been only TCR stimulated. Moreover, we also show that homeostatic cytokines have the ability to prevent the down-regulation of NKG2D expression. This down-modulation is presumably due to the interaction of NKG2D with its ligands expressed by activated T cells (Fig. 4) and by mature DC (19, 26) (data not shown). An attractive hypothesis is that the IL-15 produced by DC (26) and presented in trans by the IL-15R{alpha} (27) to naive CD8+ T cells prevents the down-regulation of NKG2D expression by the CD8+ T cells helping to prolong fitness of activated CD8+ T cells possibly by overriding down-modulation signals expected from the expression of NKG2D ligands by mature DC. Our long-term goal is to address issues raised by this hypothesis.

Mice are the experimental tool of choice for the study of the immune system in vivo. However, as 65 million years of evolution might suggest, there are significant differences between humans and mice, in both innate and adaptive immunity, and such differences should be taken into account (28). Here, distinctive from the mouse, we provide evidence that NKG2D acts as a costimulatory receptor for priming human naive CD8+ T cells, diminishing the TCR-triggering threshold and significantly affecting the functional features of the generated effector cells. Given that NKG2D ligand expression can be readily induced on DC, it seems likely that NKG2D plays an important role in the defense against infections and tumor development in humans (6, 9, 13, 14) but, not surprisingly, can also play a role in the development of autoimmunity (15, 16, 17, 18). Consequently, NKG2D could be a very good target for the development of therapies for several diseases.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Acknowledgments
 
We thank Robert Valas for cell isolation and the personnel of the flow cytometry section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, for helping with cell sorting and the National Institutes of Health blood bank for the blood samples. In addition, we are very grateful to our colleagues in the laboratory for carefully reviewing the manuscript.


   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 Address correspondence and reprint requests to Dr. Francisco Borrego, Twinbrook II Room 205, Receptor Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Drive, Rockville, MD 20852-1742. E-mail address: Fborrego{at}niaid.nih.gov Back

2 Abbreviations used in this paper: MIC, MHC class I chain-related; ULBP, UL16-binding protein; DC, dendritic cell(s); GAM, goat anti-mouse. Back

Received for publication December 15, 2004. Accepted for publication February 14, 2005.


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

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