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The Journal of Immunology, 2007, 178: 652-656.
Copyright © 2007 by The American Association of Immunologists, Inc.

CUTTING EDGE

Cutting Edge: Distinct NK Receptor Profiles Are Imprinted on CD8 T Cells in the Mucosa and Periphery during the Same Antigen Challenge: Role of Tissue-Specific Factors1

Amale Laouar2,*, Monika Manocha*, Meimei Wan*, Hideo Yagita{dagger}, Rene A. W. van Lier{ddagger} and N. Manjunath*

* CBR Institute for Biomedical Research and Department of Pediatrics, Harvard Medical School, Boston, MA 02115; {dagger} Juntendo University School of Medicine, Tokyo, Japan; and {ddagger} Academic Medical Center, Amsterdam, The Netherlands


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
NK cell receptors (NKRs) modulate T lymphocyte responses by modifying the Ag activation threshold. However, what governs their expression on T cells remains unclear. In this study we show that different NKRs are imprinted on CD8 T cells in the gut mucosa and periphery during the same Ag challenge. After a viral, bacterial, and tumor challenge, most CD8 peritoneal exudate lymphocytes expressed NKG2A but not 2B4. In contrast, most CD8 intraepithelial lymphocytes exhibited 2B4 but not NKG2A. Our data suggest that tissue-specific factors may determine the pattern of NKR expression. In the gut, CD70 licensing appears to promote 2B4 induction on mucosal CD8 T cells. Conversely, retinoic acid produced by the intestinal dendritic cells may suppress NKG2A expression. Thus, tissue-specific factors regulate NKR expression and may confer T cells with differing effector functions in a tissue and site-specific manner.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
In recent years, it has become clear that signaling through the TCR can be regulated by functionally opposing NK receptors (NKRs)3 (1, 2, 3, 4, 5, 6). Two major classes of NKRs exist in humans and mice: type I membrane proteins that belong to the Ig superfamily, such as the killer cell Ig-like receptors and gp49B1 in mice (5), and type II membrane proteins that have homology to C-type lectins, such as the CD94/NKG2A receptor (1, 2, 6). This latter receptor recognizes the nonclassical MHC molecule HLA-E (in humans) or Qa1 (in mice) and serves to inhibit T cell response (1, 2, 6). Unlike NKG2A, 2B4 does not monitor MHC class I expression but binds CD48, a molecule that is broadly expressed on immune cells (7). Although the murine 2B4 was originally described as an activating receptor on NK and T cells, studies in the recently described 2B4-deficient mice show that 2B4 functions predominantly in NK cells as an inhibitory receptor (4, 8).

NKRs are not expressed by naive CD8 T cells (2, 5, 6). However following a viral or bacterial infection, a large proportion of activated CD8 T cells in the lymphoid organs express a variety of NKRs, including gp49B1 and CD94/NKG2A, that can regulate their functions (5, 6). Although the gut mucosal CD8 T cells differ in many respects from the peripheral CD8 T cells, including function and longevity, whether they also differ in NKR expression is not known (9, 10, 11, 12). Moreover, recent studies have highlighted tissue-specific differences in the development of mucosal immunity and suggest that the local milieu may play a role in the maintenance and function of lymphocytes (12, 13, 14). In this context, we have recently reported the presence of a novel gut-specific APC of nonhemapoietic origin that constitutively expresses the costimulatory molecule CD70 (13). In addition, a recent report showed that gut-specific dendritic cells (DCs) produce retinoic acid (RA) that is essential for imprinting mucosal T cells with gut-homing specificity (14). In the present study, we show that NKRs are differentially imprinted on Ag-specific CD8 T cells in the gut compared with the periphery and examine the role of tissue-specific factors that could contribute to these differences.


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

C57BL/6 mice were purchased from The Jackson Laboratory. B6;D2-Tg(TcrLCMV)327Sdz/JDvsJ (commonly named P14) mice were purchased from Taconic Farms. All mice were maintained under specific pathogen-free conditions and used at 6–10 wk of age.

Flow cytometric analysis

Abs to mouse NKR, CD8, and {alpha}4beta7 were from BD Pharmingen. MHC Db/gp33 tetramers were obtained from Beckman Coulter. The CCR9 Ab was from R&D Systems. Gp49B1 expression was measured using the hamster IgG mAb H1.1 (15).

Viral, bacterial, and allogeneic tumor challenge

Mice were injected i.p. with 106 PFU vaccinia virus (WR strain), 104 CFU of Listeria monocytogenes (Lm) or 5 x 106 P815 or CD70-transfected P815 cells (16) and, at day 8 postinfection, their peritoneal exudate lymphocytes (PELs) and other organs were harvested.

Adoptive transfer

Naive CD8+ T cells were purified from the splenocytes of P14 mice by negative selection using the murine CD8 subset isolation kit (R&D Systems). Recipient mice were injected i.v. with 8 x 106 purified CD8 lymphocytes. At day 3 posttransfer, recipient mice were i.p. infected with 1 x 104 CFU of recombinant Lm encoding the lymphocytic choriomeningitis virus glycoprotein (rLmgp33; a gift of Dr. H. Shen, University of Pennsylvania School of Medicine, Philadelphia, PA) or with the gp33–41 peptide (KAVYNFATC, 100 µg/mouse, BioSource International) in Freund’s incomplete adjuvant and, at the indicated times postchallenge, their PELs and other organs were harvested. Isolation of lymphocytes from the intraepithelial lymphocyte (IEL) and lamina propria (LP) compartments was done as described in Ref. 13 .

Ab and RA treatment

Mice were given murine CD70 Ab (clone 3B9) (17) or hamster Ig (100 µg per i.p. injection) twice weekly. Other mice were given trans-RA (50 µl of 2 mg/ml in 16% DMSO per mouse; Sigma-Aldrich) or diluent (50 µl of 16% DMSO) twice weekly.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
Different NK receptors are expressed on CD8 T cells in the periphery and gut during the same Ag challenge

To initiate an immune response, subpopulations of CD8+ T cells may be differentially activated depending on the local environment (12, 13, 14). Because NKRs regulate T cell effector functions (2, 3, 4, 5, 6), we hypothesized that their expression may be also differentially tailored depending on the factors within the local milieu. We therefore compared the expression of various NKRs between activated CD8+ T cells in the gut and periphery. Naive T cells in the lymphoid organs in normal mice do not exhibit an activated phenotype neither do they express NKRs (2, 5, 6). However, the gut mucosal T cells from naive mice exhibit an activated phenotype (12, 13, 14). Thus we initially compared them with activated T cells that accumulate in the peritoneal cavity (PEL) after vaccinia virus infection (by the i.p. route) for NKR expression. In agreement with previous reports (2, 5, 6), a majority of CD8 T cells in the PEL expressed gp49B1 and NKG2A. However, they did not express 2B4 (Fig. 1, a and b). This NKR profile appears to be similar to activated CD8 T cells in the spleen (data not shown). In contrast, most of the gut mucosal CD8 T cells expressed gp49B1 and 2B4, but little or no NKG2A (Fig. 1a). In contrast, the Ly49 isoforms NK1.1 and DX5 were not expressed by CD8 T cells whether derived from the peritoneal cavity or gut mucosa (Fig. 1b). These results suggest that the "activated" resident CD8 T cells present in the gut mucosa of naive mice differ in the profile of NKR expression compared with the activated cells at the peripheral sites.


Figure 1
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  		FIGURE 1. NKG2A and 2B4 are differentially imprinted on CD8 T cells in the gut and periphery. a, PELs isolated from day 8 vaccinia virus-infected C57 mice and IELs from naive mice were examined for NKRs by flow cytometry. B, Mice were i.p. infected with vaccinia virus, Lm, or mastocytoma tumor P815 cells. On day 8 postchallenge, their PELs and IELs were examined for the expression of NKR profiles. Cumulative data from three to six mice are shown. Naive CD8 T cells from splenocytes, MLN, and Peyer’s patches were negative for all of these NKRs (data not shown). c, Mice were transferred with P14 CD8+ T cells and injected i.p with gp33 peptide, and on day 3 postchallenge cells from different organs were examined for the phenotype of Gp33Db tetramer+ cells. d, Cumulative data from three mice.

 
To test whether Ag challenge alters the NKR profile of mucosal T cells and to investigate whether the NKR profile of peritoneal T cells is unique to vaccinia infection or is a common feature of peripherally activated T cells, we examined CD8 T cells in the PEL and IEL compartments of mice challenged with different Ags. Animals were i.p. injected with vaccinia virus, Lm, or allogeneic tumor P815 cells and, after 8 days, PELs and IELs were tested for NKR expression. In all methods of antigenic challenge, the majority of CD8 PELs expressed gp49B1 and NKG2A but not 2B4, whereas CD8 IELs expressed 2B4 and gp49B1 but little or no NKG2A (Fig. 1b). Thus, while the induction of gp49B1 expression appears to be a general characteristic of activated CD8 T cells, the differential expression of NKG2A and 2B4 appears to be the specific hallmark of activated CD8 T cells in the periphery and mucosa.

In the experiments described earlier, NKR expression was tested on total CD8 T cells and, thus, it could not be conclusively demonstrated that Ag-specific CD8 T cells diverge in the NKR profile at different tissue sites. We addressed this question using an adoptive transfer system. Purified naive CD8+ T cells from P14 transgenic mice that were uniformly negative for 2B4, NKG2A, and gp49B1 (Fig. 1c; column labeled "Input") were adoptively transferred to C57 recipients. Three days after transfer, the mice were injected with gp33 peptide in IFA and the expression of NKR on P14 tetramer+ cells was monitored after another 3 days in different organs using gp33 tetramers. Even under these conditions, whereas the majority of tetramer+ PELs uniformly expressed gp49B1 and NKG2A but not 2B4, the tetramer+ IELs highly expressed 2B4 and gp49B1 but exhibited little or no NKG2A (Fig. 1, c and d). Thus, NKG2A and 2B4 are differentially imprinted on CD8 T cells at the peripheral and intestinal tissue sites during the same antigenic challenge. One possibility for the physiological relevance of this observation is that the divergent NKR imprinting may contribute to some of the differences in the function and longevity of mucosal T cells as compared with peripheral T cells (9, 10, 11, 12). However, in this particular case the significance of replacing NKG2A with 2B4 on mucosal CD8 T cells is not immediately apparent. Although 2B4 was originally proposed as a stimulatory NKR, recent studies using knockout animals suggest that it essentially functions as an inhibitory molecule in NK cells (4, 8). Whether it suppresses or stimulates T cells is not yet clear. Further studies of mucosal immunity in the 2B4 knockout mice should clarify whether 2B4 expressed by mucosal T cells account for an increased function of mucosal T cells.

Blockade of CD70 costimulation attenuates 2B4 expression in mucosal CD8 {alpha}beta+ T cells

We considered the possibility that the local environment may play a role in shaping the NKR repertoire in T cells by favoring the expression of specific NKRs and suppressing others. A noteworthy feature of T cell activation is the multiplicity of costimulatory mechanisms, and it is conceivable that they might also play a role in regulating the NKR expression. In fact, costimulatory molecules appear to hold the key to determining the nature and magnitude of the T cell activation process (13, 18, 19, 20). In line with this view, we have recently identified a novel gut-specific APC of nonhemopoietic origin that constitutively expresses the CD70 costimulation molecule and showed that a blockade of the CD70 pathway attenuates the activation and expansion of mucosal CD8+ T cells (13). Thus, in an attempt to identify the mechanism leading to the differential expression of 2B4 and NKG2A, we tested the ability of CD70 costimulation to regulate this process. In the initial experiments, C57 mice were orally challenged with Lm and simultaneously i.p. injected with either control Ig or blocking CD70 Abs. As Fig. 2, a–c show, the expression of 2B4 was drastically decreased in CD8{alpha}beta+ but not in CD8{alpha}{alpha}+ IELs in CD70 Ab-treated animals. Because very small numbers of activated CD8 T cells could be found at the systemic site of PELs using this route, we could not conclusively prove that anti-CD70 Ab had no effect on NKR expression on the PEL CD8 T cells. To extend the experiment reported above and confirm whether the effect of anti-CD70 was specific to the expression of 2B4 or also to other NKRs, we repeated the CD70 Ab treatment in adoptive transfer experiments (Fig. 2d). Even in this setup, the CD70 Ab treatment did not change the NKR expression pattern of tetramer+ PELs (not shown). However, although CD70 Ab treatment significantly reduced the total number of tetramer+ cells in the IEL compartment (Fig. 2d) as reported earlier (13), it also substantially reduced 2B4 expression on the tetramer+ cells that were still present (Fig. 2d). In this context, one possibility for the effect of CD70 Ab on 2B4 expression is that this Ab may have interfered with CD40-dependent activation (19, 20). It was shown that in the absence of CD4 help, the CD70 expression on APCs plays a key role in CD40-dependent CD8 T cell activation (20). It is therefore possible that the CD4-helped CD8 cells are the ones that still migrate, accumulate, and express 2B4 in the anti-CD70-treated animals, whereas the CD70/CD40-dependent CD8 cells are not activated properly and, as a secondary effect, also fail to induce 2B4 in the gut environment.


Figure 2
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  		FIGURE 2. CD70 Ab treatment abrogates 2B4 expression in CD8 IELs and a deliberate CD70 costimulation induces 2B4 expression in CD8 PELs. a, Mice were infected orally with Lm. On days 0, 2, 4, and 6 postinfection the mice were injected i.p with 100 µg of control hamster IgG or blocking CD70 Ab, and on day 8 postinfection IELs were stained with Abs to CD8beta and 2B4. b, Mice were infected and treated with CD70 Ab as in a and examined for 2B4 expression on {alpha}{alpha}+ and {alpha}beta+ CD8 T cells. c, Cumulative data from 3 mice with SD. d, Mice were transferred with naive P14 CD8+ T cells and 3 days later were i.p. injected with gp33 peptide. On the day of the transfer, the day of the Ag challenge, and 2 days later, the mice were also i.p. injected with control hamster IgG or CD70 Ab. On day 3 after Ag-challenge the IELs were examined for the NKR phenotype of tetramer+ cells. Asterisks indicate statistical significance that was calculated between the total GP33Db+ cells and the 2B4+ GP33Db cells of the anti-CD70-treated animals using Student’s t test. e, Mice were i.p. injected with P815 or P815-CD70 cells, and on day 8 postchallenge their CD8-PELs were examined for the presence of 2B4. Cumulative data with SD from three mice are also shown.

 
Challenge with CD70-expressing tumor cells induces 2B4 expression on CD8 PELs

To directly investigate whether CD70 costimulation is involved in 2B4 induction, we tested whether 2B4 expression by peripheral CD8 T cells can be enhanced by the provision of CD70 during stimulation. Mice were challenged with tumor P815 cells or CD70-transfected P815 cells and, 8 days later, PELs were harvested and examined for the expression of NKRs. As expected, most CD8+ PELs were positive for NKG2A and gp49B1 receptors (not shown). More importantly, deliberate CD70 costimulation enhanced dramatically the number of 2B4+ CD8+ PELs (~6-fold greater) (Fig. 2e). Thus, it appears that CD70 costimulation is necessary for the induction of 2B4 by CD8 T cells. Because gut-specific CD70+ APCs stimulate the mucosal T cells in situ (13), we suggest that tissue-specific APCs may be responsible for the differential induction of 2B4 by T cells. However, considering that mature DCs at systemic sites also express CD70 and can bypass CD4 T cell help (19, 20), the 2B4 induction may not be entirely mediated by gut-specific CD70+ APCs.

RA down-regulates NKG2A expression

Although our previous results could account for 2B4 induction by mucosal CD8 T cells, they failed to reveal how NKG2A is shut off in the mucosa. We considered the possibility that NKG2A may be actively suppressed in the gut microenvironment. It has been recently shown that RA produced by DCs in the intestinal lymphoid organs can alter specific gene expression in T cells to imprint gut-homing specificity (14). We therefore examined whether external provision of RA can alter NKG2A expression by peripherally activated CD8 T cells. In the initial experiments mice were infected i.p. with Lm, and on day 5 postinfection cells isolated from the peritoneal cavity (expressing NKG2A uniformly) were in vitro cultured with 20 ng/ml IL-2 in the presence or the absence of 100 nM trans-RA for 2 days. This concentration of RA was shown to be optimal for the expression of the gut homing molecules on activated T cells (14). As Fig. 3 a shows, a significant reduction in the number of NKG2A+ CD8+ cells was observed in the RA-treated samples compared with the controls, suggesting that NKG2A down-regulation can be achieved with RA treatment. To test whether RA treatment in vivo also suppresses NKG2A, we i.p. infected mice with Lm and simultaneously i.p injected them with RA or the diluent (DMSO). Although the CD8 T cell numbers and the profile of 2B4 expression was unaltered in both compartments, the number of NKG2A+ as well as CD94+ cells significantly decreased in the PEL of RA-treated animals (Fig. 3b and data not shown), showing that NKG2A/CD94 expression can be selectively down-regulated on CD8 T cells by RA treatment. We also confirmed this observation on activated splenocytes (data not shown) and Ag-specific P14 CD8 T cells (Fig. 3c). In these experiments and consistent with the previous report (14), we found that RA treatment up-regulated the expression of CCR9 and {alpha}4beta7 on Ag-specific CD8+ T cells in the PEL (~5- to 14-fold greater percentage of positivity and ~2 to 4-fold greater mean fluorescence intensity). More importantly, we found that RA treatment significantly attenuated the expression of NKG2A on Ag-specific CD8+ T cells in the PEL (Fig. 3c), suggesting that RA actively suppresses TCR-induced up-regulation of NKG2A expression. Moreover, we have investigated in vitro activation of P14 CD8 T cells with DCs from the spleen and mesenteric lymph node (MLN) in the presence or absence of 10 µM citral, a blocker of RA synthesis, (as described in Ref. 14). Activation with gp33-pulsed splenic DCs induced a robust induction of NKG2A expression on P14 CD8 T cells (~60%), and treatment with citral had no significant effect on the level of this expression. In contrast, activation with MLN-DC induced only a weak expression of NKG2A on activated CD8 (~18%), and treatment with citral enhanced this expression to a level that is similar to the one observed with splenic DCs.


Figure 3
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  		FIGURE 3. Trans-RA down-regulates NKG2A expression in vitro and in vivo. a, Mice were i.p. infected with Lm and 5 days later their PELs were harvested and cultured in vitro for 2 days with 100 nM RA or diluent (DMSO) and examined for the presence of NKG2A. b, Mice were i.p infected with Lm. On days 0, 3, and 6 postinfection the mice were also i.p. injected with RA or diluent (DMSO), and 2 days later CD8 T cells from the PEL and IEL compartments were examined for NKG2A expression. c, Mice were transferred with P14 CD8+ T cells. On day 3 posttransfer mice were i.p. injected with recombinant Lm gp33. On days 0, 3, and 6 postinfection the mice were i.p. injected with RA or DMSO, and 2 days later tetramer+ cells accumulating in the PEL and IEL compartments were examined for NKG2A and 2B4 expression. The percentage and mean fluorescence intensity of 2B4 and NKG2 expression by tetramer+ cells are shown. Cumulative data from three mice with SD are shown. Asterisks indicate the statistical significance (*, p < 0.05).

 
In summary, our results suggest that the pattern of NKR expression by activated CD8 T cells differs between peripheral and gut mucosal sites and that the tissue-specific factors may be involved in shaping this pattern. These results highlight the importance of the microenvironment in generating diversity in NK receptor profiles that can potentially regulate effector activity in a tissue- and site-specific manner. This may be particularly important in the intestine, where the immune system has to delicately balance the induction of tolerance with the active immunity.


   Acknowledgments
 
We thank D. Vargas for help with rodent i.v. injection procedure and Dr. Hao Shen for providing the rLmgp33 Listeria strain.


   Disclosures
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 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 National Institutes of Health Grant AI46566 and Senior Research Award from the Crohn’s and Colitis Foundation of America (to N.M.). Back

2 Address correspondence and reprint requests to Dr. Amale Laouar, CBR Institute for Biomedical Research, 800 Huntington Avenue, Boston. MA 02115. E-mail address: laouar{at}cbr.med.harvard.edu Back

3 Abbreviations used in this paper. NKR, natural killer receptor; DC, dendritic cell; IEL, intraepithelial lymphocyte; Lm, Listeria monocytogenes; LP, lamina propria; MLN, mesenteric lymph node; PEL, peritoneal exudate lymphocyte; RA, retinoic acid. Back

Received for publication December 8, 2005. Accepted for publication October 31, 2006.


   References
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 Abstract
 Introduction
 Materials and Methods
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 Disclosures
 References
 

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