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Originally published online as doi:10.1189/jlb.0707496 on October 16, 2007

Published online before print October 16, 2007
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(Journal of Leukocyte Biology. 2008;83:106-111.)
© 2008 by Society for Leukocyte Biology

Distinct receptor repertoire formation in mouse NK cell subsets regulated by MHC class I expression

Yoshihiro Hayakawa*,1,2, Sally V. Watt*, Kazuyoshi Takeda*,{dagger} and Mark J. Smyth*,2

* Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and
{dagger} Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

2 Correspondence: Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia, 3002. E-mail: yoshihiro_hayakawa{at}merck.com or mark.smyth{at}petermac.org


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ABSTRACT
 
The acquisition of inhibitory MHC-specific receptors occurs during NK cell differentiation and has been considered important in regulating NK cell responsiveness. NK cell differentiation has been studied on the basis of cell surface phenotype, function, and proliferative capacity. Together with phenotypically immature Mac-1lo NK cells, the mature Mac-1hi NK cell pool can be dissected further into two functionally distinct CD27hi and CD27lo subsets. Two major inhibitory receptors, CD94/NKG2A and Ly-49, are expressed on mouse NK cells. The acquisition of the CD94/NKG2A receptor seems to be an early event, whereas Ly-49 receptor expression is considered a relatively late event during NK cell ontogeny. In this study, we demonstrated a distinct NK cell inhibitory receptor repertoire formation within mature NK cell populations as defined by Mac-1 and CD27. By analyzing mice deficient in MHC class I expression or NKG2D ligand transgenic mice, we have shown that the inhibitory receptor repertoire can be modulated according to the differentiation/maturation status of NK cells, and the receptor acquisition is imprinted at an early stage of NK cell development by MHC class I interactions.

Key Words: maturation • differentiation


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INTRODUCTION
 
Multiple stages of NK cell development have been studied on the basis of their cell surface phenotype, function, and proliferative capacity [1 , 2 ]. We have shown recently in mice that the mature Mac-1hi NK cell pool can be dissected further into two functionally distinct CD27hi and CD27lo subsets [3 ]. Together with phenotypically immature Mac-1lo NK cells, these mature NK cell subsets show distinct characteristics. NK cells distinguish abnormal cells by using a repertoire of Ig-like and C-type lectin receptors that deliver a balance of inhibitory and activating signals [4 , 5 ]. A number of activating receptors recognize ligands on transformed and virus-infected cells and thus, stimulate NK cell cytokine production (e.g., IFN-{gamma}) [6 ], secretion of cytotoxic granules [7 ], and expression of TNF superfamily death-inducing ligands [8 ], which effectively control virus infection and tumor initiation and spread [9 10 11 ]. Although the original "missing self" hypothesis was that NK cells attack cells that fail to express a sufficient level of self-MHC class I molecules [12 ], the simple absence of self-MHC class I molecules is insufficient to explain the important role target ligands also play in activating NK cells in an immune response.

It is more important that there is no clear conclusion as to how NK cells control their self-reactivity during lineage differentiation and maturation, although several models have been proposed. One model proposed by Yokoyama and colleagues [13 ] was termed the "licencing" model, as engagement of inhibitory receptors specific for self-MHC molecules licences NK cells to undergo a terminal maturation step. Another model, coined the "at least one" model suggests that the formation of the NK cell repertoire is regulated by the acquisition of at least one inhibitory receptor specific for one or another self-MHC class I molecule [5 , 14 , 15 ]. To explain the hyporesponsiveness of NK cells further, it has been proposed that the developing NK cells that fail to recognize self-MHC ligands by their inhibitory receptor appear "disarmed" by an active mechanism to dampen their responsiveness [16 , 17 ]. In all cases, there seems to be a strong correlation between NK cell maturation/differentiation and the acquisition/expression of inhibitory receptors. Although the acquisition of NK cell receptors is considered an important process to regulate NK cell responses, little is known about the receptor repertoire of NK cells at different maturation stages. It is interesting that we have recently shown a distinct expression profile of Ly-49C and I compared with other Ly-49 family members (A, G2, D) on mature mouse CD27hi and CD27lo subsets [3 ]. As the CD27hi NK cell subset can differentiate further into the CD27lo NK cell subset, whereas the CD27lo subset appears to be stable [18 , 19 ], Ly-49C and I expression on mature NK cell subsets may be linked to their stages of differentiation. Here, we report that NK cell receptor repertoire formation can be modulated according to their maturation or differentiation status, and further, the receptor acquisition might be imprinted at an early stage of NK cell development by MHC class I interactions. These results indicate that NK cell inhibitory receptor repertoires can be edited, even at the mature stage of their differentiation, and the positive or negative interaction of NK cells may be involved distinctly in this receptor-editing process.


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MATERIALS AND METHODS
 
Mice
In-bred wild-type C57BL/6 (B6 WT) mice were purchased from The Walter and Eliza Hall Institute of Medical Research (Melbourne, Australia). B6 TAP-1–/–, B6 β2M–/–, B6 Rae-1 transgenic (Rae-1 Tg; kindly provided by Prof. Lewis Lanier, UCSF, San Francisco, CA, USA) [20 ], and B6 Rag–2–/– common {gamma} chain–/– (Rag–/–c{gamma}–/–) mice were bred and maintained at the Peter MacCallum Cancer Centre (Victoria, Australia). All experiments were performed according to animal experimental ethics committee guidelines.

Reagents
Antibodies to TCRβ (H57–597), NK1.1 (PK136), CD11b (M1/70), CD27 (LG.3A10), CD94 (18d3), Ly-49C/I (5E6), and KLRG1 (2F1) were purchased from BD PharMingen (San Diego, CA, USA) and eBioscience (San Diego, CA, USA).

Flow cytometry
For staining NK cells, splenic mononuclear cells were first preincubated with CD16/32 (2.4G2) mAb to avoid the nonspecific binding of antibodies to Fc{gamma}R. Then, the cells were incubated with a saturating amount of mAb. Flow cytometric analysis was performed with a LSR II instrument (BD Biosciences, San Jose, CA, USA).

Adoptive transfer
NK cells were enriched from spleen by auto MACS (mouse NK cell isolation kit, Miltenyi Biotec, Auburn, CA, USA) and transferred (5x105) into B6 Rag-2–/–c{gamma}–/– mice i.v. Cells from spleen were harvested 2 weeks after transfer and stained for NK1.1, TCRβ, Mac-1, CD27, Ly49C/I, and CD94. NK cells were determined by electronic gating on NK1.1+ TCRβ– cells.

In vivo NK cell activation
Mice were injected i.p. with 2 µg {alpha}-galactosylceramide ({alpha}-GalCer; kindly provided by Pharmaceutical Research Laboratories, Kirin Brewery, Gumna, Japan) or 200 µg polyinosinic:polycytidylic [poly(I:C); Sigma Chemical Co., St. Louis, MO, USA]. Cells were harvested from spleen 2 days after the injection and subjected to flow cytometry analysis.

Statistical analysis
Data were analyzed for statistical significance using the Student’s t-test. P values less than 0.05 were considered significant.


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RESULTS
 
Positive and negative interactions distinctly regulate NK cell maturation and receptor repertoire
In mice, mature Mac-1hi NK cells can be divided into two functionally distinct Mac-1hi CD27hi (referred to as CD27hi in this study) and Mac-1hi CD27lo subsets (referred to as CD27lo in this study), as distinct from phenotypically immature Mac-1lo CD27hi NK cells (referred to as Mac-1lo in this study). We first investigated the role of activating and inhibitory interactions in the formation of CD27hi and CD27lo NK cell subsets by examining mice deficient in TAP-1 or β2M, therefore lacking MHC class I expression, or mice with ubiquitous transgenic expression of the NKG2D ligand, Rae-1{epsilon} [20 ]. There were alterations in the NK cell subset formation in mice lacking TAP-1 and β2M and in mice overexpressing Rae-1, as CD27hi NK cells represented a higher proportion of total NK cells in these mice compared with WT mice (Fig. 1 ). It is interesting that TAP–/–mice showed an even greater proportion of CD27hi NK cells than β2M–/– mice, alhough both strains lack class I molecule expression. Nevertheless, these results indicate a potential contribution of inhibitory and activating receptors in controlling NK cell subset formation and differentiation in vivo. Acquisition of NK cell receptors is considered to be an important process that regulates NK cell responses and may also be linked to NK cell maturation. Therefore, we investigated the inhibitory receptor repertoire further at different stages of NK cell maturation. There are two major types of inhibitory receptors expressed by NK cells: the Ly-49 family and the CD94/NKG2A inhibitory receptor complex, which have been implicated in NK cell self-tolerance [1 , 2 ]. Furthermore, we have reported recently that CD27hi and CD27lo NK cell subsets showed distinct Ly-49C and I expression amongst other Ly-49 family members (including A, G2, D) [3 ]. By using this inhibitory receptor expression profile and the maturation marker CD27, NK cells can be divided into four receptor subsets: single-positive (SP), expressing Ly49C/I or a higher level of CD94 (CD94hi); double-positive (DP), expressing Ly49C/I and CD94hi; and double-negative (DN), expressing no Ly49C/I and a lower level of CD94 (CD94lo). In WT mice, CD94hi SP NK cells clearly dominated the Mac-1lo subset, which is known to represent an earlier, immature stage of NK cell differentiation. However, following subsequent NK cell maturation steps, the CD94 SP cells were a minor subpopulation in Mac-1hi CD27hi and CD27lo subsets (Fig. 2 ). By contrast, Ly49C/I SP and DP NK cells were minor populations amongst Mac-1lo NK cells but dominant populations within the Mac-1hiCD27lo NK cell pool (Fig. 2) . These results imply that the inhibitory receptor repertoires can be actively modified during NK cell differentiation/maturation. We then determined whether NK cell activating and inhibitory receptor interactions may play a role in the repertoire formation at different stages of NK cell maturation by examining the same populations in TAP–/–, β2M–/–, and Rae-1 Tg mice. Although overexpression of Rae-1 did not demonstrate any impact on NK cell repertoire formation, TAP–/– and β2M–/– mice showed a significant alteration in their receptor repertoire amongst NK cell subsets (Fig. 2) . NK cells from TAP–/– and β2M–/– mice had a greater proportion of Ly49C/I SP or DP cells at the Mac-1lo stage, suggesting that Ly-49C/I acquisition may be permitted at an earlier stage of NK cell differentiation in the absence of MHC expression (Fig. 2) . Such a trend was even conserved in the total NK cell population and later stages of NK cell differentiation, as a higher proportion of DP NK cells was also observed within the Mac-1hiCD27lo subset.


Figure 1
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  		Figure 1. The role of activating and inhibitory receptors in NK cell subset formation. Cells isolated from the spleens of B6 WT, TAP-1–/–, β2M–/–, and Rae-1 Tg mice were stained for the NK cell maturation markers Mac-1 and CD27, together with NK1.1 and TCRβ. (A) The dot-plots shown are profiles for Mac-1 and CD27 expression on electronically gated NK1.1+ TCRβ– cells. (B) The data represent the percentage of NK cell subset ± SD (n=3–4). Data are representative of two experiments. *, P < 0.05, compared with WT mice.


Figure 2
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  		Figure 2. The inhibitory receptor repertoire can be modified during NK cell differentiation by MHC class I expression. Cells isolated from the spleens of B6 WT, TAP-1–/–, β2M–/–, and Rae-1 Tg mice were stained for Ly-49C/I and CD94, together with NK1.1, TCRβ, Mac-1, and CD27. (A) The dot-plots shown are expression patterns for Ly-49C/I and CD94 on total NK cells (NK1.1+ TCRβ– cells) or indicated NK cell subsets (Mac-1lo, CD27hi, CD27lo), electronically gated on the relevant population as shown. (B) The data represent the percentage of NK cell repertoire ± SD (n=3–4). Data are representative of two experiments. *, P < 0.05, compared with WT mice.

NK cell receptor repertoire formation is imprinted at an early differentiation stage in the absence of MHC class I
There is some strong evidence indicating that once a NK cell receptor gene is activated, its expression is stably maintained in the cell, even if it undergoes multiple rounds of proliferation [21 , 22 ]. To determine whether the distinct NK cell receptor repertoires observed in MHC class I-deficient hosts are regulated by a cell-intrinsic pathway, we transferred splenic NK cells from WT or β2M–/– mice into MHC class I-intact lymphopenic Rag-2–/–c{gamma}–/– mice. As TAP–/– mice (but not β2M–/– mice) showed a distinct subset formation in addition to their unique inhibitory receptor repertoire, we chose β2M–/– mice as more suitable to investigate the influence of host MHC class I expression on inhibitory receptor repertoire formation. NK cells from β2M–/– mice reconstituted in the Rag-2–/–c{gamma}–/– recipient showed a greater proportion of DP cells, regardless of their maturation status, but this phenotype became most obvious at the later stages of differentiation (e.g., CD27lo subset; Fig. 3 ). These results show that lineage-committed NK cells in MHC class I-deficient hosts will retain their predefined receptor repertoire even when transferred into the MHC class I-intact host.


Figure 3
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  		Figure 3. Altered NK cell receptor repertoires in MHC class I-deficient hosts maintained after adoptive transfer. MACS-enriched NK cells were isolated from spleen and transferred (5x105) into B6 Rag-2–/–c{gamma}–/– mice. Cells from spleen were harvested 2 weeks after the transfer and stained for NK1.1, TCRβ, Mac-1, CD27, Ly49C/I, and CD94. (A) The dot-plots shown are expression patterns for Ly-49C/I and CD94 on total NK cells (NK1.1+ TCRβ– cells) or indicated NK cell subsets (Mac-1lo, CD27hi, CD27lo), electronically gated on the relevant population as shown. (B) The data represent the percentage of NK cell repertoire ± SD (n=3). Data are representative of two experiments. *, P < 0.05, compared with WT mice.

NK cell activation causes selective CD27hi subset expansion but does not alter receptor repertoire
It is widely recognized that NK cells can be activated rapidly by various stimuli in vitro or in vivo; however, little is known about NK cell populations after their activation in the context of maturation or differentiation status. Poly(I:C) and {alpha}-GalCer are known to activate NK cells potently through a TLR-dependent/type I IFN pathway [23 ] or invariant NKT cell-dependent/IFN-{gamma}-mediated mechanism [24 ], respectively. To determine NK cell phenotype following in vivo activation, we examined the expression of NK cell maturation markers following in vivo activation by poly(I:C) or {alpha}-GalCer. Amongst all NK cells, the CD27hi subset was dominant after in vivo poly(I:C) or {alpha}-GalCer injection (Fig. 4 4A ), suggesting that CD27hi NK cells were the most prevalent population within in vivo-activated NK cells. To determine further whether there was any repertoire preference in activated NK cells, we next examined the inhibitory receptor expression on the CD27hi NK cell subset after in vivo activation. As the NK cell receptor repertoire was not altered upon poly(I:C) or {alpha}-GalCer activation amongst CD27hi NK cells (Fig. 4B) , there did not appear to be any preferential stimulation or expansion of a SP, DP, or DN Mac-1hiCD27hi NK cell subset upon in vivo NK cell activation.


Figure 4
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  		Figure 4. CD27hi NK cells predominate after in vivo activation. Cells isolated from the spleens of naïve B6 WT and poly(I:C)- or {alpha}-GalCer-treated mice were stained for Ly-49C/I and CD94, together with NK1.1, TCRβ, Mac-1, and CD27. The dot-plots shown are profiles for Mac-1 and CD27 expression on electronically gated NK1.1+ TCRβ– cells (A) or expression patterns for Ly-49C/I and CD94 on CD27hi NK cell subsets (B). The data represent the percentage of positive cells ± SD (n=3). Data are representative of two experiments. *, P < 0.05, compared with naïve mice.


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DISCUSSION
 
In general, the formation of heterogeneous subsets of mature leukocytes is crucial for the immune system to maintain a broad range of response to pathogen while controlling reactivity to self. Mature Mac-1hi NK cells can be dissected into two functionally distinct subsets by the expression of CD27, and those subsets show distinct responses to cytokine and stress-ligand stimulation [3 , 25 ]. It has been widely recognized that NK cells play an important role at the early stage of immune responses against virus infection or tumor cells [10 , 11 ]. In these immune responses, NK cells can be activated by various stimulation, including cross-talk with other immune cells, such as APC. The function of NK cells is quickly up-regulated upon in vivo stimulation, whereby they exert potent cytotoxic activity and/or production of inflammatory cytokines, such as IFN-{gamma}.

It is well known that MHC class I plays a pivotal role in regulating the response of NK cells [15 , 26 ]. Expression of β2M is required for the normal expression levels of MHC class I on the cell surface [27 28 29 ], and indeed, NK cells from those mutant mice are known to be self-tolerant (reviewed in ref. [17 ]). The activating NKG2D receptor expressed on all NK cells binds to ligands with structural homology to MHC class I, such as the mouse Rae-1 family [4 ]. The transgenic expression of Rae-1 is known to alter NK cell responsiveness, as chronic exposure to Rae-1 can cause the impairment of NKG2D-mediated NK cell responses by simple down-regulation of NKG2D expression [20 , 30 ]. Thus, this evidence implies that an imbalance of positive and negative signaling pathways can alter NK cell responsiveness. We found some alterations in the formation of NK cell subsets in the absence of MHC class I expression or under chronic stimulation of the NKG2D pathway. Considering that CD27lo NK cells are a late stage of NK cell differentiation [3 , 18 ], the balance of inhibitory and activating interactions may play a partial but as-yet undefined role in the final stages of NK cell maturation. In addition, we observed some differential impact of β2M or TAP-1 deficiency on NK cell maturation. This may reflect the fact that the β2M molecule is associated with molecules other than MHC class I, such as CD1d. Of note, β2M–/– and TAP-1–/– were targeted in 129-derived ES cells, and although mice were backcrossed extensively (10 times) to B6 background, it remains possible that other MHC loci may not match the B6 background completely between the strains. Nevertheless, future studies will be required to determine whether β2M-associated molecules, other than MHC class I, distinctly regulate NK cell maturation. We also describe that the inhibitory receptor repertoire is quite diverse in NK cell subpopulations. There was a clear trend that early Mac-1lo NK cells preferentially expressed CD94/NKG2A, whereas Ly-49C/I expression became more predominant at the Mac-1hiCD27lo stage. Furthermore, the NK cell population expressing CD94hi and Ly-49C/I (DP) also became more dominant at the CD27lo stage. There was a significantly larger proportion of DP cells amongst the Mac-1lo NK cells in the absence of MHC class I expression compared with WT or Rae-1 Tg mice, and such a trend was even more obvious at later stages of differentiation. Taken together, these results implicate two possible mechanisms by which NK cells acquire inhibitory receptor expression during their maturation: Ly-49 inhibitory receptor expression is acquired mainly at later stages of NK cell maturation; or NK cells expressing Ly-49 or both inhibitory receptors (DP) are somehow preferentially proceeding to full maturation. It is interesting that a continuous interaction between inhibitory receptors and MHC class I molecules may not be necessary, as NK cells from β2M–/– mice still showed the ability to reconstitute a high frequency of DP cells in the MHC class I-intact host. Thus, the NK cell receptor repertoire is presumably imprinted at an early differentiation stage.

Recent studies have revealed that NK cells require the engagement of one or more stimulating receptors to be activated [4 , 17 ]. To regulate self-responsiveness of NK cells, the stimulating signals from the activating receptor should be countered by a negative regulatory signal through inhibitory MHC class I-specific receptors. The ligands for NK cell activation are expressed by normal cells as well as by transformed or infected cells (reviewed in ref. [5 ]). Such capacity of NK cells to also recognize ligands on normal cells highlights the importance of mechanisms to regulate NK cell self-responsiveness or induce self-tolerance. Several pieces of evidence support the concept that NK cells achieve self-tolerance by the expression of at least one receptor specific for self-MHC class I molecules acquired in a stochastic manner [5 ]. However, a recent study demonstrated that a substantial population of mature splenic NK cells in B6 mice lacks the expression of all of self-MHC class I-specific inhibitory receptors (Ly49C/I and CD94/NKG2A) [16 ]. Despite lacking the expression of self-MHC class I-specific inhibitory receptors, these DN NK cells showed diminished responses to self, and it is unclear whether this was a result of the expression of unidentified, H-2b-specific inhibitory receptors [16 ]. In addition, we observed that the DN population was predominant at earlier stages (Mac-1lo) rather than late stages (CD27lo) of NK cell maturation. It is interesting that there was some reduction of DN cells in the absence of MHC class I molecules within mature CD27hi and CD27lo NK cell subsets. This suggests that NK cell receptors can be modulated during NK cell differentiation/maturation, and MHC class I expression is actively involved in this editing process. Further, we show that CD27hi NK cells become the predominant population in the total NK cell pool after in vivo NK cell stimulation with poly(I:C) or {alpha}-GalCer. It is also possible that Mac-1lo NK cells may be activated in vivo, but considering that CD11bhiCD27lo cells are a product of CD11bhiCD27hi NK cells (as we have shown in previous studies [18 , 19 ]), it is more likely that CD11bhiCD27hi cells are the most responsive subset to in vivo NK cell activation [18 ]. In addition, we observed further that there was no particular preference in the receptor repertoire generated compared with that seen amongst naïve CD27hi NK cells. Therefore, these results indicate that the CD27hi NK subset can predominate after in vivo stimulation, and its receptor repertoire can be maintained even after such stimulation.

It has been proposed that the acquisition of inhibitory MHC class I-specific receptors occurs in a sequential manner during NK cell differentiation. In mice, the acquisition of the CD94/NKG2A receptor is an early event, whereas Ly-49 receptor expression is a relatively late event during NK cell ontogeny. It has been reported that Ly-49 receptors are initially expressed after birth [21 , 31 , 32 ], and then, the proportion of NK cells expressing the Ly-49 receptor increases over the first few weeks of life, with some exceptions [33 ]. In contrast, the CD94/NKG2A receptor complex is even expressed on fetal NK cells [22 , 25 , 31 , 32 , 34 ]. Together with those previous findings, our current data strongly suggest that NK cell receptor acquisition can be imprinted at an early stage of NK cell development by MHC class I interactions and later modulated, according to their maturation or differentiation status. Considering the important role of target ligands that trigger NK cell activation in the immune responses in concert with their inhibitory receptor recognition, NK cells might control their self-reactivity, even at a relatively late stage of their lineage differentiation and maturation by editing their inhibitory receptor repertoire.


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ACKNOWLEDGEMENTS
 
We thank Koetsu Ogasawara and Lewis Lanier for providing Rae-1 transgenic mice. We also thank Mark Shannon, Ralph Rossi, Rachel Cameron, Shannon Griffiths, and the staff of the Animal Facility at Peter MacCallum Cancer Centre for their generous support.


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FOOTNOTES
 
1 Current address: Pharmacology, Tsukuba Research Institute, Merck-Banyu Co. Ltd., 3 Okubo, Tsukuba, Ibaraki, Japan, 300-2611. Back

Received July 26, 2007; revised September 10, 2007; accepted September 14, 2007.


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