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. 2013 Mar 25;10(3):222–229. doi: 10.1038/cmi.2013.2

Interaction between natural killer cells and regulatory T cells: perspectives for immunotherapy

Isabela Pedroza-Pacheco 1, Alejandro Madrigal 1, Aurore Saudemont 1
PMCID: PMC4012769  PMID: 23524654

Abstract

Regulatory T (Treg) cells and natural killer (NK) cells are key players in the immune system. The interaction between these two cell types has been reported to be beneficial in healthy conditions such as pregnancy. However, in the case of certain pathologies such as autoimmune diseases and cancer this interaction can become detrimental, as Treg cells have been described to suppress NK cells and in particular to impair NK cell effector functions. This review aims to discuss the recent information on the interaction between Treg cells and NK cells under healthy and pathologic conditions, to describe the specific conditions in which this interaction takes place, the effect of Treg cells on hematopoietic stem cell differentiation and the consequences of this interaction on the optimization of immunotherapeutic protocols.

Keywords: differentiation, effector functions, natural killer cells, regulatory T cells

Introduction

Natural killer (NK) cells and regulatory T (Treg) cells are two cell types that play important roles in the immune system. NK cells are characterized as CD56+CD3− lymphocytes that are part of the innate immune system, and the first line of defense against viruses and tumors. They recognize tumor cells or pathogen-infected cells through different mechanisms, including downregulation of major histocompatibility complex (MHC) class I molecules on target cells (missing self theory)1 and/or upregulation of proteins such as NKG2D ligands on ‘distressed' cells (induced self theory).2 Once the target is recognized, NK cells react by releasing cytokines and recruiting other immune cells, predominantly via interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) secretion or directing cytotoxic activity. Cytotoxicity can be subdivided into natural cytotoxicity, which does not require prior stimulation, and antibody-dependent cell cytotoxicity or ADCC, where antibody-coated target cells are recognized by CD16 on NK cells and eliminated.

By contrast, Treg cells are part of the adaptive immune system and maintain immune self-tolerance. There are several CD4+ T-cell subsets3 described that induce tolerance—T regulatory 1 and 3, T helper 2 and CD4+CD25highFOXP3high Treg cells; however, we will only focus on the latter in this review. CD4+CD25highFOXP3high Treg cells can be further subdivided into natural Treg (nTreg) cells, which are thymus-derived and induced Treg (iTreg) cells, which are periphery-derived and can be induced by maturation of CD4+ T cells ex vivo.4 Both nTreg cells and iTreg cells suppress target cells directly via galectin-1,5 interleukin (IL)-106 or IL-357,8 or by depriving the milieu of IL-2, thus inhibiting T-cell proliferation.9 Moreover, it has been suggested that activated human Treg cells can express granzyme A and kill effector cells.10 Finally, Treg cells can mediate suppression in a cell-contact-dependent manner via transforming growth factor-beta (TGF-β) as shown by Nakamura et al.11 Treg cells also suppress immune cells indirectly through CD3912 or by acting on antigen-presenting cells (APC) via CTLA-4,13,14 LAG-315 or NRP-1.16 They have been described to suppress CD4+ T cells,17 CD8+ T cells,18 NK cells,18 B cells,19 dendritic cells,20 mast cells21 and NK T cells.22 Here we summarize the latest information on the effects of the interaction of NK cells and Tregs cells during pregnancy, autoimmune diseases, cancer and on hematopoietic stem cells (HSC).

Interaction between NK cells and Treg cells during pregnancy

There is accumulating evidence that the interaction between NK cells and Treg cells could be beneficial during pregnancy. This may be due to the requirement of an immunosuppressive environment for the successful implantation of the embryo and tolerance of the mother to the embryo. The uterine endometrium, also called the decidua, is crucial for the development of placental vasculature. Interestingly, 70% of all human decidual lymphocytes are NK cells, defined as uterine or decidual NK (dNK) cells.23 In comparison to peripheral blood NK cells, dNK cells are characterized as CD56brightCD16−CD3−, express killer cell immunoglobulin-like receptors and exhibit low killing capacity despite the presence of cytolytic granules.24 In addition, a higher frequency of CD4+CD25bright Treg cells that express a high level of CTLA-4 has been observed in the decidua of pregnant women as compared to non-pregnant women.25 Because of this finding, the impact of Treg cells on preeclampsia and spontaneous abortion was studied. Sasaki et al.25 showed that the frequency of CD4+CD25bright Treg cells in the decidua of women who had suffered spontaneous abortion was considerably reduced in comparison to those of healthy pregnant women; however, this was not the case for preeclampsia. In fact, in that case, an impaired systemic expansion of iTreg cells causing a difference in Treg cell composition was noted.26 In addition, it has been described that dNK cells, when interacting with CD14+ cells in decidual tissues, promote a tolerant environment by inducing Treg cell proliferation.27

These findings were recently confirmed by Hsu et al.26 who proposed a model of tolerance induction during pregnancy where CD14+DC-SIGN+APC highly express the tolerogenic molecules, HLA-G and ILT4, possibly stimulated by IL-10. These APC induce the conversion of CD4+ T cells into iTreg cells, which suppress conventional T cells. In contrast, in the case of preeclampsia, these APC exhibit reduced HLA-G and ILT4 expression, possibly due by a reduction in soluble IL-10. This causes a decline of iTreg proliferation, which may be partially rescued by peripheral blood nTreg cells; hence the presence of more nTreg numbers than in healthy pregnant women. This model may suggest the importance of soluble factors to promote tolerance, like IL-10, as previously mentioned, or TGF-β. TGF-β has been described as a factor capable of converting NK cells into dNK cells28 with high proliferation rates in vitro. These results highlight the importance of NK cells, Treg cells and soluble factors in promoting and maintaining a tolerant environment during pregnancy.

Interaction between NK cells and Treg cells in autoimmune diseases

To date, no studies have directly assessed the impact of the interaction between NK cells and Treg cells in autoimmune diseases. However, it has been observed that there is a dynamic, bi-directional regulation between NK cells and CD4+ T cells. In an experimental model of autoimmune myasthenia gravis, NK cells proliferated to control autoreactive CD4+ T cells at early stages of the disease. Later, as the autoimmune disease progresses, T cells produce IL-21, leading to NK cell degeneration and reduction in NK cell function and numbers.29 Furthermore, in a mouse model of relapsing remitting multiple sclerosis, it was showed that, before or after the induction of the disease, blocking IL-21 caused an exacerbated response of inflammatory cells into the central nervous system and impairment of Treg cell homeostasis and function.30 Moreover, this study highlighted that a reduced CD4+CD25+FOXP3+ Treg cell number, reduced FOXP3 expression and functionality enhanced the proliferation of autoreactive CD4+ T cells. This was later confirmed by the same group where IL-21R Fc successfully reduced Treg cell numbers in a FOXP3GFP/GFP mice. These findings lead us to suggest that Treg cells may be responsible for NK cell suppression, since IL-21 promotes suppressive function while blocking this cytokine promotes exaggerated CD4+ T-cell responses. However, further studies need to be performed to understand, if an interaction between NK cells and Treg cells has an impact in autoimmune diseases and particularly, if IL-21 plays a role as we suggested.

Impact of the interaction between NK cells and Treg cells for immunotherapy

Interaction between NK cells and Treg cells in cancer

Increased frequency of Treg cell number has been directly correlated to cancer progression. As widely reviewed by Orentas et al.,3 a detectable increase in Treg cell number was observed in several types of cancer where the number of Treg cells was inversely correlated to the frequency and function of NK cells. For example, Ghiringhelli et al.31 observed a high Treg cell number versus a low number of NK cells that were also dysfunctional in gastrointestinal stromal tumor-bearing patients. Other studies showed similar results with colon32 and prostate carcinoma33 where activating NKG2D receptor expression was decreased on NK cells concomitant with the detection of high levels of TGF-β, possibly secreted by the tumor, allowing Treg cell proliferation and a tolerant environment. Similarly, Betts et al.34 studied Treg cell activity before tumor excision and 12 months later in a cohort of patients with colorectal cancer. They observed higher levels of FOXP3 in CD4+CD25high Treg cells in patients compared to healthy controls that returned to normal levels later after tumor excision. Cai et al.35 showed functional impairment of circulating and intrahepatic NK cells in hepatocellular carcinoma patients. Significant NK cell reduction was observed in tumor regions compared to non-tumor regions in the liver. Peripheral NK cells demonstrated reduced killing capacity against K562 target cells and reduced IFN-γ secretion in vitro, which was further correlated to a high incidence of CD4+CD25+ Treg cells. The addition of Treg cells from hepatocellular carcinoma patients efficiently inhibited the anti-tumor ability of autologous NK cells in vitro. In fact, further investigations showed that elevated Treg cell numbers are associated with elevated levels of TGF-β.36

How do Treg cells suppress NK cells?

The effect of Treg cells on NK cells has been extensively reviewed by Zimmer et al.37,38 To fully understand how and in which conditions Treg cells may suppress NK cells, the findings of different studies relating to the impact on NK cells, the cell source, ratios used and possible mechanisms of suppression are summarized in Table 1. It is noteworthy to comment on the following points.

Table 1. Effects of Treg cells on NK cell functions.

NK cell function Human Mouse Ratio NK∶Treg Type of Tregs   Mechanism of Supression
Natural cytotoxicity Inhibited in resting NK cells.31   1∶1 Resting nTregs Allo Membrane-bound TGF-β
  Not inhibited if IL-2Rγ-chain cytokines present.31   1∶1 Resting nTregs Allo  
  Inhibited in NK cells with APC presence.18   1∶1 Activated nTregs Auto Membrane-bound TGF-β
    Inhibited in resting NK cells.69,70 1∶1 Activated nTregs Auto Membrane-bound TGF-β
    Inhibited in IL-12 activated NK cells.41 1∶1 Activated iTregs Auto Membrane-bound TGF-β
    Inhibited in resting NK cells.71 1.5∶1 Activated nTregs Allo  
  Enhanced in resting and IL-2 activated NK cells with APC presence.42   1∶2 Tumor-specific activated iTregs Auto Cell-cell contact
Cytokine production Inhibited if IL-12 present.31   1∶1 Resting nTregs Allo Solub. TGF-β
  Not inhibited if IL-2/IL-15 present.31   1∶1 Resting nTregs Allo Solub. TGF-β
  Inhibited in NK cells with APC presence.18   1∶1 Activated nTregs Auto  
    Inhibited in IL-12 activated NK cells.41 1∶1 Activated iTregs Auto Membrane-bound TGF-β
  Inhibited if IL-2 present.42   1∶2 Tumor-specific activated iTregs Auto Cell-cell contact
Activating receptors NKG2D downregulation in resting NK cells (resting Treg cells).31   1∶1 Resting nTregs/activated nTregs Allo Membrane-bound TGF-β
    NKG2D dowregulation in resting NK cells (activated Tregs).31 1∶1 Resting nTregs/activated nTregs Allo Membrane-bound TGF-β
  NKG2D and NKp44 downregulation in IL-2 activated NK cells.42   1∶2 Activated nTregs and tumor-specific activated iTregs Auto Cell-cell contact
Proliferation Decreased proliferation by half in presence of APC.72   1∶1 iTregs and nTregs Auto  
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Abbreviations: Allo, allogeneic; APC, antigen-presenting cells; Auto, autologous; IL, interleukin; iTreg, induced Treg; NK, natural killer; nTreg, natural Treg; Solub, soluble; Treg, regulatory T.

Firstly, TGF-β was the mechanism of suppression identified in most studies. The majority of these studies agreed that TGF-β in its membrane form, but not the soluble form, was the main mechanism of NK cell suppression. However, other mechanisms of suppression have not been fully studied regarding this specific interaction. TGF-β plays an important role in suppression of NK cells but may not be the only mechanism.

Secondly, allorecognition or Treg TCR stimulation is essential for suppression. As expected, in vitro coculture studies of human allogeneic Treg cells with resting NK cells show a decrease in NK cell natural cytotoxicity, cytokine production and expression of some activating receptors such as NKG2D.31 Upon TCR stimulation, Treg cells are able to suppress both autologous and allogeneic NK cells, even though some studies have observed low expression of membrane bound TGF-β in activated Treg cells.39

Thirdly, Treg cell suppression can be blocked by the presence of IL-2, IL-4, IL-7 and supraphysiological doses of IL-12. It would be interesting to explore whether the presence of IL-15 also overrides the suppression of NK cells by Treg cells because of its importance in NK cell therapy for cancer patients.40 In hematopoietic stem cell transplantation (HSCT) we could hypothesize that an inflammatory setting with high concentration of cytokines such as IL-2 would allow NK cell-mediated immune responses to occur without suppression by Treg cells.

Finally, the effect of iTreg cells on NK cells has been described for the first time by Zhou et al.41 who described NK cell suppression by iTreg cells in the presence of IL-12 in vitro. Furthermore, Bergmann et al.42 studied the role of tumor iTreg cells in the modulation of NK cell function and reported that in the presence of tumor iTreg cells and IL-2, expression of NKG2D, NKp44 and production of IFN-γ was downregulated in NK cells. However, in the presence of tumor cells, iTreg cells increased NK cell cytotoxicity, which could also be enhanced by IL-2, highlighting a synergistic effect that may be useful for optimizing therapies for disease clearance. Figure 1 summarizes the effect of Treg cells on NK cells in different conditions, as previously mentioned.

Figure 1.

Figure 1

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Effect of Treg cells on NK cell function. Treg cells suppress NK cells through membrane bound TGF-β in allogeneic resting conditions (a) or when Treg cells are activated for example by APC, in both autologous and allogeneic settings (b). However, NK cells overcome this suppression in a cytokine milieu, such as IL-2 (c). Furthermore, antigen-specific iTregs enhance NK cell functions. This effect can be synergized with the addition of IL-2 (d). APC, antigen-presenting cells; IFN-γ, interferon-gamma; IL, interleukin; iTreg, induced Treg; NK, natural killer; TGF-β, transforming growth factor-beta; Treg, regulatory T.

Effects of Treg cell depletion on NK cells

Because of the effect that Treg cells have on NK cells and other cells that are crucial for patient survival, many groups focused on depleting Treg cells before or after treatment. Table 2 summarizes some of the relevant work that has been performed in mice and humans. It is clear that depletion of Treg cells can lead to increased NK cell functions and proliferation, which is further enhanced by IL-2 and possibly IL-15 therapy, although the latter has yet to be investigated.

Table 2. Studies using Treg cell depletion in humans and mice.

NK cell function   Source Ref.
Natural cytotoxicity Increased (twofold) (ex vivo) Mice 31, 73
  No effect when CD25 depletion only, but effect in CD25 depletion+IL-2 (long-term assays) Mice 74
  Enhanced in metastatic lymph node (ex vivo) Human 31
  Enhanced in tumor kidney carcinoma (ex vivo) Human 31
Proliferation Increased in spleen (ex vivo) Mice 31
Tumor clearance Decreased tumor size Mice 69, 71, 73, 75
  Increased number of tumor-free mice Mice 76
Graft rejection Increased bone marrow rejection Mice 77
Survival Increased survival when IL-2 infused Mice 74
Tumor regression Promote tumor regression with the addition of IL-2 Mice 78
Disease remission To skew the patient towards graft versus leukemia instead of graft versus host disease Human 79
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Abbreviation: IL, interleukin.

Many groups deplete Treg cells to restore NK cell functions. When chemotherapy fails, low oral doses of cyclophosphamide in advanced chemotherapy-resistant cancers provide a selective reduction of Treg cells, while restoring NK cell activity.43 Another group tried to inactivate Treg cells in mice through OX40 triggering, a costimulatory receptor from the TNF family. Eighty per cent of the mice that received the intra-tumor injection of the agonist anti-OX40 monoclonal antibody OX86 rejected the tumor.44 Similarly, CTLA-4 and PD-1 may block Treg cell activity.45,46 Furthermore, anti-cancer agents such as Lenalidomide and Pomalidomide are potential candidates for inhibition of proliferation and function of Treg cells47 while promoting the activation of NK cells.48

A reciprocal regulation between NK cells and T cells has been suggested.49 In fact, Brillard et al.50 reported the efficacy of autologous IL-2-activated NK cells in humans and in mice for blocking iTreg cell proliferation (2∶1 NK/Treg cell ratio) via high levels of IFN-γ, skewing the environment towards Th1 polarization. Similarly, Roy et al.51 found that NK cells inhibited the conversion of FOXP3+ cells but not nTreg cells during a response to microbial antigens in healthy individuals through NKG2D. Furthermore, Chin et al.52 suggested that when NK cells are depleted in mice, there was a significant expansion of nTreg cells favored by a systemic environment with low levels of IL-6 and high levels of TGF-β. These observations may suggest that nTreg cells can suppress natural cytotoxicity; yet activated NK cells may override this effect by producing high amounts of IFN-γ, inducing an environment that does not allow Treg cells to proliferate and augment tolerance.

Interaction between NK cells and Treg cells in hematopoietic stem cell transplantation

In HSCT settings, NK cells play a critical role. They confer protection against infections and provide graft versus leukemia interactions, which is the recognition and further killing of residual recipient malignant cells by allogeneic donor cells, first described by Ruggeri et al.53 A delayed T-cell recovery but early reconstitution of NK cells has been reported in cord blood (CB) transplanted patients with hematological malignancies.54 In addition, studies from Beziat et al.55 demonstrated that NK cells that reconstitute early after CB HSCT are fully functional, being able to kill leukemic cells ex vivo and exhibiting a normal NK cell repertoire. Although previous reports show absence of CD4+ T cells in early reconstitution after CB HSCT,54 others suggest the presence of residual donor T cells including Treg cells after HSCT depending on the conditioning used.56,57,58 These studies highlighted the survival of Treg cells and the possibility that these cells create a tolerant environment that may have an impact on NK cells which is crucial for early responses after HSCT.

In HSCT, HSC migrate to the bone marrow where hematopoiesis occurs. The differentiation and cell cycle of these cells is dictated by signals provided within the bone marrow, called the niche. Several authors59,60,61 have proposed TGF-β as a molecule that induces ex vivo hibernation causing HSC dormancy, a mechanism that regulates cell cycle, differentiation and apoptosis of HSC, in other words, suppressing differentiation and proliferation of HSC until they are required. Additionally, studies62,63 have shown that the effect observed on HSC depends on the concentration of TGF-β. As a result, high concentrations of TGF-β cause inhibitory effects while low concentrations cause stimulatory effects.

In a mouse model of HSCT64 high frequency of Treg cells were observed in the endosteal surface of the bone marrow in close proximity to HSC, compared to the spleen and lymph nodes. To further investigate the impact of Treg cells on HSC viability, Treg cells were depleted and surprisingly, the absence of Treg cells led to a 70%–90% reduction of donor cells. These results suggest a positive effect on HSC by facilitating allogeneic tolerance. Furthermore, Challen et al.65 studied the effect of TGF-β on genetically distinguishable myeloid and lymphoid HSC populations. Instead of maintaining HSC dormancy, they demonstrated, that in transplanted mice, TGF-β1 promotes myeloid HSC differentiation rather than lymphoid HSC differentiation, which could potentially affect NK cell differentiation. In this context, it is important to remember the biphasic characteristics that TGF-β may have according to concentration. What about NK cell differentiation? A recent article from Marcoe et al.66 demonstrated that TGF-β limits NK cell numbers in mice by controlling NK cell maturation. In fact, in the absence of TGF-β, ontogenic maturation from HSC to NK cells was faster. This might suggest that TGF-β-mediated Treg cells may be one of the factors responsible for NK cell immaturity, for example in CB and in neonatal immunity.

In fact, recent work published by Rörby et al.67 demonstrated the impact on CB HSC of a protein involved in the signaling cascade of TGF-β called SMAD4. They used a lentiviral overexpression technique and observed that CB HSC overexpressing SMAD4 were more susceptible to TGF-β and therefore presented higher levels of growth arrest and apoptosis in vitro. This effect was confirmed by blocking TGF-β type I receptor, which restored proliferation. Interestingly, they also observed that mice injected with HSC overexpressing SMAD4 had impaired long-term rather than short-term engraftment. This may suggest that TGF-β, through SMAD4, may have an effect on long-term engraftment of HSC. Also, PU.1, a transcription factor involved in NK cell differentiation and maturation, was downregulated when SMAD4 was overexpressed in HSC, an effect that could severely compromise NK cell differentiation.

There is currently no information about the effects of Treg cells on NK cell differentiation, but preliminary results from our group suggest a strong impairment of NK cell differentiation when activated Treg cells are present in vitro (unpublished data). It would be interesting to determine the effects of Treg cells on NK cells at the molecular level, in particular on transcription factors such as T-bet that regulate HSC differentiation into NK cells and NK cell maturation in addition to the previously mentioned PU.1.68 The effects of Treg cells on HSC and potentially on NK cell differentiation are summarized in Figure 2.

Figure 2.

Figure 2

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Hypothesis of the effects of Treg cells on HSC and NK cell differentiation. TGF-β can promote the differentiation of myeloid progenitors rather than lymphoid progenitors. Furthermore, Treg cells may affect late stages of NK cell differentiation through TGF-β in addition to affecting NK cell IFN-γ, perforin and granzyme B production. T-bet and PU.1 expression could be affected by TGF-β signaling and hampered NK cell differentiation and functions. CLP, common lymphoid progenitor; HSC, hematopoietic stem cell; IFN-γ, interferon gamma; MLP, myeloid progenitor, NK, natural killer; NKP, NK progenitor, iNK, immature NK, mNK, mature NK; TGF-β, transforming growth factor-beta; Treg, regulatory T.

Conclusions

NK cells, Treg cells and their interplay have crucial roles in healthy physiology, as well as in some pathological conditions. During pregnancy, NK cells, Treg cells and soluble factors like IL-10 and TGF-β seem to act together in a positive feedback loop to create a tolerant environment. Failure to do so may cause obstetrical diseases. In the case of autoimmune diseases, it may be that IL-21 mediated Treg cells lead to NK cell suppression. While in cancer, and particularly in HSCT, strong evidence suggests that a high number of Treg cells is correlated to poor prognosis. Therefore, a lot of research effort is currently dedicated to the design of new strategies to deplete Treg cells, such as blocking CTLA-4 and PD-1. However, the removal of Treg cells may also have severe implications. For example, in HSCT, it can lead to increased mortality caused by an uncontrolled reaction of donor T cells. Therefore, it is imperative to gain a better understanding of the conditions in which Treg cell suppression takes place to allow the design of therapies that will preserve the positive effects of both NK cells and Treg cells. The understanding of the impact of their interactions with each other and with other cell types, such as in conjunction with APC, will provide valuable information that may improve cell therapy efficacy.

Acknowledgments

Work in the authors' laboratory is supported by Anthony Nolan. I Pedroza-Pacheco is the recipient of a CONACyT fellowship. The authors kindly thank Dr Steve Cox for proof reading.

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