Our immune system has white blood cells that migrate throughout the body in search of invading microbes or diseased and damaged cells. When these events are encountered, the white blood cells move into the affected tissue and launch an immune response to eliminate the threat.

Natural killer cells are white blood cells that kill cells that are infected with viruses or are cancerous. Most of what is known about conventional natural killer cells is derived from studying the spleen, which filters the blood and contains many immune cells. Natural killer cells also circulate around the body or are found within other tissues, and it was thought that both types of cells were either the same, or that one type could develop into the other. However, the thymus—an organ that is another source of white blood cells—contains a sub-population of natural killer cells that are distinct from the conventional splenic natural killer cells. Furthermore, recent work revealed the existence of two types of natural killer cells within the liver: some of these cells were similar to the conventional splenic natural killer cells that circulate throughout the body, while others appeared to be ‘tissue-resident’ natural killer cells that were poised to deliver an immune response.

Now Sojka et al. show that the tissue-resident natural killer cells found in the liver are a distinct lineage of cells. These cells mature independently from the conventional natural killer cells found in the spleen, and the natural killer cells found in the thymus. Moreover, the skin contains tissue-resident natural killer cells similar to those in the liver; whilst natural killer cells that had previously been discovered in the uterus were shown to contain a fourth distinct tissue-resident lineage.

The work of Sojka et al. will encourage a full re-evaluation of the roles played by natural killer cells to determine which populations of these cells are responsible for implementing immune responses. Furthermore, a more thorough understanding of how tissue-resident natural killer cells function to eliminate diseased or damaged cells, such as cancerous cells, could also contribute to future efforts to develop new anti-cancer treatments.

Immune cells migrate throughout the body where they search tissues for pathological events induced by invading pathogens or emerging tumors, for example. Upon encounter with these events, circulating immune cells stop and respond in collaboration with yet other immune cells, often in organized lymphoid tissues. The subsequent orchestrated host immune response controls the pathological process by directing relevant immune cells to the damaged tissue. In contrast to circulating immune cells are tissue-resident immune cells which already reside in selected organs where they appear to be poised to deliver immune responses. However, how tissue-resident immune cells contribute to host responses is less well understood and will be aided by identifying factors that distinguish circulating and tissue-resident immune cells.

Natural killer (NK) cells are components of the innate immune system (Yokoyama, 2013). Initially described on the basis of their inherent capacity to kill tumor cells without prior sensitization, NK cells are now known to participate in a wide variety of immune responses, such as early control of viral infections. In addition, they can respond to pro-inflammatory cytokines by producing yet other inflammatory cytokines, such as interferon-γ (IFNγ), their signature cytokine that can influence adaptive immune cells.

NK cells require IL-15 and its cognate receptor, IL-15R, for development (Cao et al., 1995; DiSanto et al., 1995; Suzuki et al., 1997; Lodolce et al., 1998; Kennedy et al., 2000). In knockout mice lacking IL-15 or any chain of the trimeric IL-15R (α, β, γ), splenic NK cells are absent. The development of splenic NK cells is thought to occur largely if not exclusively in the bone marrow (BM) where cells committed to the NK cell lineage undergo a series of putative developmental stages, characterized by acquisition and loss of various surface markers, including cytokine receptors, NK cell receptors, and integrins (Kim et al., 2002; Yokoyama et al., 2004; Di Santo, 2006). Out in the periphery, mature splenic NK cells can be further distinguished by differential expression of CD11b and CD27 (Kim et al., 2002; Hayakawa and Smyth, 2006). Thus, conventional splenic NK cells display developmental markers associated with maturation.

NK cells require certain transcription factors for development (Hesslein and Lanier, 2011), in particular NFIL3 (E4BP4), described as the NK cell-specification factor (Di Santo, 2009). Mice lacking NFIL3 have essentially no splenic NK cells though other organs were not thoroughly examined (Gascoyne et al., 2009; Kamizono et al., 2009; Kashiwada et al., 2010). The related t-box transcription factors, Tbet (Tbx21) and eomesodermin (Eomes), play more complex roles in NK cell development (Townsend et al., 2004; Gordon et al., 2012). In the absence of Tbet, splenic NK cells display an immature phenotype, and a subpopulation of NK cells in the liver is absent, consistent with overlapping and cooperative roles of Tbet and Eomes in NK cell development. Alternatively, Tbet may direct the development of a separate lineage of NK cells. Current data cannot definitively distinguish between these possibilities for the role of Tbet and Eomes in NK cell development.

Classically studied in the mouse spleen and expressing the NK1.1 antigen on CD3ε-negative cells, NK cells are also present in solid organs, such as the thymus, uterus, and liver (Yokoyama, 2013). Like the conventional NK (cNK) cells in the spleen, thymic NK cells are cytotoxic and require IL-15 but they differ from cNK cells by their characteristic expression of CD127 (IL-7 receptor α) and requirement for a thymus where they can arise from early thymocyte precursors (Vosshenrich et al., 2006; Ribeiro et al., 2010; Vargas et al., 2011). Furthermore, thymic NK cells uniquely require the transcription factor GATA-3 for development (Vosshenrich et al., 2006). NK cells are normally present in the non-pregnant uterus (Parr et al., 1991; Yadi et al., 2008; Mallidi et al., 2009) but have been mostly studied after they expand at the site of embryo implantation during pregnancy (Moffett and Loke, 2006; Hatta et al., 2012). Like cNK cells, uterine NK (uNK) cells require IL-15 for development (Ashkar et al., 2003). In addition, they are cytotoxic as they express perforin and granzymes, and they produce IFNγ (Parr et al., 1990; Ashkar et al., 2000). Interestingly, however, uNK cells appear relatively normal in Tbet-deficient mice (Tayade et al., 2005) and recent studies suggest that a subset of uNK cells can be distinguished from cNK cells (Yadi et al., 2008). Thus, NK cell subsets can be identified in different tissues that appear to be distinguishable from cNK cells.

In the liver, we recently showed that there are two populations of NK cells, distinguished by mutually exclusive expression of CD49a and DX5 (Peng et al., 2013). Phenotypically, CD49a⁻DX5⁺ are very similar to splenic cNK cells whereas CD49a⁺ DX5^– are unlike splenic cNK cells. In parabiotic mice, the host liver contains CD49a⁺ DX5⁻ NK cells of host origin and circulating CD49a⁻DX5⁺ NK cells derived from both host and the other parabiont, indicating that the CD49a⁺ DX5⁻ cells are tissue-resident NK (trNK) cells whereas the CD49a⁻DX5⁺ cells are cNK cells. The trNK cells appear similar to immature cNK cells because they express similar markers (NK1.1, NKp46) but low levels of CD11b, are DX5⁻, and display high levels of TNF-related apoptosis-inducing ligand (TRAIL) (Kim et al., 2002; Di Santo , 2006; Peng et al., 2013). However, the liver trNK cells appear to be distinct from immature BM cNK cells because they are cytotoxic and express CD49a. Nonetheless, the liver trNK cells could represent an intermediate cell stage in the development of mature splenic cNK cells from NK cell precursors.

Consistent with this possible developmental intermediate stage, there is a complete absence of TRAIL⁺ NK cells in the livers of Tbet-deficient mice (Gordon et al., 2012). Importantly, this analysis was done before the CD49a⁺ DX5⁻ trNK cells in the liver were described. Therefore, while the subset of TRAIL⁺ liver NK cells lacking in Tbet-deficient mice could represent a failure of maturation of cNK cells, an alternative interpretation of these results is that there may be two different NK cell lineages, one of which is completely Tbet-dependent.

The current data therefore suggest that there are three possible origins of the liver trNK cells. (1) They could be related to thymic NK cells because GATA-3-deficient NK cells are defective in homing to the liver (Samson et al., 2003). (2) They could represent an intermediate stage in the development of NK cell precursors into mature splenic NK cells. (3) They could represent an alternative NK cell lineage, distinct from both cNK and thymic NK cells. If these relationships can be resolved, it will then be important to determine how liver trNK cells are related to other trNK cells, such as uNK cells, and to the expanding list of innate lymphoid cells (ILCs) (Spits and Cupedo, 2012; Spits et al., 2013).

Herein we examined the liver trNK cells in detail with respect to thymic NK, splenic cNK, and trNK cells in other organs. Based on phenotypic characteristics and transcription factor requirements, our studies support the presence of at least four populations of NK cells: cNK (spleen and circulating), thymic, liver (and skin) trNK cells, and uNK cells. Furthermore, these studies indicate that trNK cells can be distinguished from each other and from ILCs.

Many immune cell lineages migrate throughout the body via the circulatory system. However, emerging data indicate that a number of different immune cell types appear to be tissue-resident and rarely recirculate. Here we demonstrate that NK cells are also comprised of circulating and several tissue-resident cell types in the liver, skin and uterus. Our comprehensive transcriptome and FACS analyses on liver trNK cells and liver and splenic cNK cells suggested that they may be distinct lineages of NK cells. Indeed, circulating liver and splenic cNK cells were absent in NFIL3-deficient mice, further demonstrating their lineage relationship to each other. On the other hand, NFIL3-deficient mice still possessed trNK cells in the liver, skin, and uterus. Moreover, Tbet-deficient mice lacked trNK cells in the liver and skin but uterine trNK cells and cNK cells in the liver and spleen were largely intact. Finally, thymic NK cells represent a distinct NK cell lineage because they are absent in nude and GATA-3-deficient mice which generally possess cNK and trNK cells. Taken together, these data suggest that there are at least four lineages of NK cells: cNK cells circulating in spleen, blood and other organs, thymic, and two trNK cell lineages—liver (and skin), and uterine.

The trNK cells can be distinguished from cNK cells in several different ways. Most importantly, trNK cells do not require the putative NK cell specification factor, NFIL3 (Di Santo, 2009; Gascoyne et al., 2009; Kamizono et al., 2009; Kashiwada et al., 2010), indicating that they belong to a different cell lineage. In the liver, skin, and uterus, they differentially express CD49a, though it is possible that trNK cells in other organs preferentially express another marker. Concomitantly, they lack DX5 expression which is generally expressed as a late maturation marker on most cNK cells (Kim et al., 2002; Peng et al., 2013). Interestingly, trNK cells from unmanipulated mice display markers associated with cNK cell activation, such as CD69, in contrast to cNK cells which do not express CD69 until activated (Karlhofer and Yokoyama, 1991; Wang et al., 2000). The trNK cells also express a different repertoire of Ly49 receptors, suggesting that they may be tolerant to self by using mechanisms that do not strictly employ MHC class I-dependent licensing by Ly49 receptors, as has been shown for cNK cells in the spleen (Kim et al., 2005; Elliott and Yokoyama, 2011). The trNK cells efficiently produce other cytokines, particularly TNFα and GM-CSF which may contribute to inflammatory conditions in a manner distinct from cNK cells which predominantly produce IFNγ. TNFα production occurs following stimulation by target cells and also occurs in trNK cells producing IFNγ. Finally, trNK cells utilize a separate set of transcription factors which may endow trNK cells with other unique functions, in addition to lineage commitment. As such, due to their tissue localization and these distinctive features, trNK cells most likely play important roles in innate defense in ways that should be distinguishable from cNK cells. Future investigations to re-examine the contribution of NK cells in different organs with a focus on trNK cells should reveal these roles.

Among the various NK cell lineages, the liver and skin trNK cells appear to be highly related. They are phenotypically similar and both are absent in Tbet-deficient mice. Although it remains to be formally shown that a common precursor can give rise to liver and skin trNK cells but not other NK cell lineages, these data indicate that they are more related to each other than to other NK cell lineages, including cNK cells. uNK cells appear distinct from the liver and skin trNK cells because they are Tbet-independent, even though all are NFIL3-independent. Perhaps this is due to concomitant expression of Eomes at high levels in uNK cells (Tayade et al., 2005). Alternatively, uterine trNK cells may depend on other transcription factors unique for this NK cell lineage.

The liver, skin, and uterine trNK cell lineages can be distinguished from thymic NK cells in several ways. Both trNK (as shown here) and cNK cells do not express high levels of CD127 that is characteristic of thymic NK cells (Vosshenrich et al., 2006; Yadi et al., 2008). Moreover, thymic NK cells are absent in nude mice and in mice lacking GATA-3 which possess cNK cells, as recapitulated here. By contrast, we showed liver trNK cells are present in nude and GATA-3 deficient mice, suggesting that skin trNK cells will show these features, although the skin and uterine trNK cells need to be further studied in these mice. The trNK cells in the uterus in virgin mice as studied here will also need to be studied with respect to other subsets of uNK cells which have been described previously, including endometrial vs decidual NK cells, and NK1.1^– DX5^– uterine NK cells (Yadi et al., 2008; Mallidi et al., 2009).

Inasmuch as liver, skin, and uterine trNK cells can be distinguished from cNK cells, it is important to note that they do share some important similarities, in addition to surface expression of NK1.1 and NKp46 but not CD3ε. As shown here and previously published, cNK, uterine and liver trNK cells can respond to YAC-1 targets by degranulation and killing (Kiessling et al., 1975; Linnemeyer and Pollack, 1991; Peng et al., 2013), though this needs to be further detailed for the skin trNK cells described here. Moreover, cNK cells require IL-15 or IL-15Rα (Lodolce et al., 1998; Kennedy et al., 2000) and here we showed that IL-15Rα-deficient mice have no cNK or trNK cells, such that no NK1.1⁺ CD3⁻ cells were identifiable in spleen, liver, and skin of the knockout mice. Similarly, IL-15-deficient mice lack NK1.1⁺ CD3⁻ cells in the uterus (Ashkar et al., 2003; Barber and Pollard, 2003), indicating that trNK cells in the uterus as well as liver and skin are IL-15Rα-dependent. While more detailed analysis of the progenitors for NK cells will be required to establish the precise lineage relationship of trNK and cNK cells to each other, current data, particularly cytotoxic potential and IL-15-dependence, support their intimate relationship, despite differences in transcription factor requirements.

Recent studies indicate that cNK cells are related to innate lymphoid cells (ILCs) (Spits and Cupedo, 2012; Spits et al., 2013). While this area of research is fluid with potentially more cells to be identified and additional characteristics to be discovered, it now appears that ILCs can be separated into three groups, based on shared characteristics (Spits et al., 2013). cNK cells are now classified as belonging to the group 1 ILCs, due to their shared production of IFNγ. cNK cells can be distinguished from other group 1 ILCs by their cytotoxic capacities, dependence on IL-15, and general lack of IL7Rα expression, features shared between cNK and liver, skin, and uterine trNK cells. Recently, a new IFNγ-producing ILC1 cell was identified which demonstrated dependence on NFIL3, Tbx21, and IL-15 but not IL-15Rα (Fuchs et al., 2013), unlike the trNK cells described here. Finally, while the relationship of thymic NK cells expressing CD127 to ILCs which also express CD127 may need further refinement, current knowledge suggest that the liver (skin) and uterine trNK cells are more related to cNK cells than ILCs.

Future studies, however, may continue to blur the lines between ILCs and NK cells. Already, it has been noted that markers previously thought to be exclusively expressed on NK cells, such as NKp46, are expressed on ILCs that now can be distinguished from classical NK cells (Walzer et al., 2007; Cella et al., 2009; Spits et al., 2013). A further confounding issue is the apparent plasticity of ILCs with potential interconversion between ILC groups (Cella et al., 2010; Vonarbourg et al., 2010), indicating the increasing complexities of definitively identifying ILC types and potentially distinguishing ILCs from other immune cells. Thus, it is possible that trNK cells may be more closely related to certain ILCs than currently appreciated.

Tissue-resident NK cells are more closely related to ILCs in that both the trNK cells and the ILCs have extended their place of residency outside the traditional secondary lymphoid organs. Originally most ILCs were considered in the context of gut or lymphoid tissues (Spits and Cupedo, 2012) but recently they have been identified in other nonlymphoid tissues such as the skin and the uterus. ILC2s in the skin have been reported to regulate cutaneous inflammation but they are unaffected by IL15-deficiency (Roediger et al., 2013), unlike trNK cells as shown here. In the uterus, immature NK cells have been described as well as a phenotypically related but distinct population of cells that express the transcription factor RORC and produce IL-22, suggesting that they may be ILC3s rather than NK cells (Crellin et al., 2010; Male et al., 2010). Additional studies will be needed to more finely localize the anatomic location of trNK cells in these tissues and the transcription factors required for their development and maintenance, work that will be aided by development of new tools to distinguish trNK cells from cNK cells and ILCs.

The trNK cells should also be considered in the context of other non-lymphoid tissue-resident immune cells, including NKT cells, tissue-resident memory T cells, γδ T cells, B1 B cells, and tissue macrophages, among others. Of these, NKT cells are of special interest because they share several characteristics with trNK cells in the liver. NKT cells were first identified because they express markers associated with NK cells, such as NK1.1, but are not cNK cells because they express rearranged TCR genes (Bendelac et al., 2007). While they are now known to recognize glycolipids presented by CD1 molecules, a large number of NKT cells also reside in the liver, though they can be found in other tissues. In the liver, NKT cells crawl within the sinusoidal space by patrolling sinusoidal endothelial cells (Geissmann et al., 2005). This is reminiscent of early electron microscopy studies of the rat liver which identified ‘pit cells’, now recognized as NK cells (Wisse et al., 1976; Bouwens et al., 1987). Pit cells are found in the sinusoidal space usually adjacent to sinusoidal endothelial cells. Although liver trNK cells have not been formally examined vis-à-vis pit cells, it seems likely that they are related, if not equivalent.

The trNK cell populations also are potentially related to tissue-resident memory T cells which had been previously activated by antigen-stimulation and differentiated into effector cells that then reside in non-lymphoid tissues (Sheridan and Lefrancois, 2011; Gebhardt et al., 2013). Our studies indicate that trNK cells appear to have an activated phenotype with expression of CD69 and other activation markers as well as other phenotypic changes. However, it is not yet clear if trNK cells differentiate from a circulating precursor that then differentiates into a cell taking up tissue residency, akin to tissue-resident memory T cells (Masopust et al., 2010). Our studies do not rule out this possibility although the transcription factor requirements make it unlikely that a putative circulating precursor is an NK cell that had previously differentiated into a cNK cell.

An alternative possible origin of trNK cells is a progenitor that seeds the peripheral organs during embryonic or fetal life. In particular, due to early hematopoiesis occurring in the fetal liver, liver trNK cell precursors may seed the liver during embryonic life. In this regard, it is interesting to note that Ly49E was first noted to be almost exclusively expressed on fetal NK cells (Toomey et al., 1998). However, recent findings (Filtjens et al., 2013) and those reported here indicate that liver trNK cells in adult mice also selectively express Ly49E, raising the possibility that Ly49E⁺ NK cells in the fetus reflect trNK cells already present in the embryonic liver, at a time when cNK cells are poorly developed (Bukowski et al., 1985; Dorfman and Raulet, 1998). As such, since the liver is the major site for fetal hematopoiesis, Ly49E⁺ NK cells may not reflect fetal NK cells per se but instead the possibility that precursor of trNK cells seeds the liver during early life. Consistent with this possibility, we recently showed that precursors of liver trNK cells are present in the adult liver (Peng et al., 2013). Moreover, adult BM hematopoietic stem cells do not fully reconstitute the liver trNK cell population in irradiated mice. Thus, precursors of trNK cells, like γδT cells and certain tissue macrophages (Havran and Allison, 1990; Schulz et al., 2012), may seed tissues early in life, a topic that will require further evaluation.

In conclusion, we provide molecular evidence that trNK cells are distinct from circulating cNK cells in their cytokine profiles, expression of NK cell receptors and most importantly their transcription factor requirements. Their tissue residency feature suggests that they have tissue-specific homeostatic functions. Our studies should prompt a re-examination of the myriad roles of NK cells in many immune responses which could be due to trNK cells, rather than cNK cells. Finally, our studies may also be applicable to emerging data on other hematopoietic cells that circulate throughout the body in that there may be related but distinct cell types that are tissue-resident.

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Author details

1. Dorothy K Sojka

   Rheumatology Division, Washington University School of Medicine, St. Louis, United States

   Contribution

   DKS, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Beatrice Plougastel-Douglas

   Rheumatology Division, Washington University School of Medicine, St. Louis, United States

   Contribution

   BP-D, Conception and design, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

3. Liping Yang

   Rheumatology Division, Washington University School of Medicine, St. Louis, United States

   Contribution

   LY, Conception and design, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

4. Melissa A Pak-Wittel

   Rheumatology Division, Washington University School of Medicine, St. Louis, United States

   Contribution

   MAP-W, Conception and design, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

5. Maxim N Artyomov

   Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States

   Contribution

   MNA, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

6. Yulia Ivanova

   Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States

   Contribution

   YI, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

7. Chao Zhong

   Molecular and Cellular Immunoregulation Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States

   Contribution

   CZ, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

8. Julie M Chase

   Rheumatology Division, Washington University School of Medicine, St. Louis, United States

   Contribution

   JMC, Conception and design, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

9. Paul B Rothman

   The Johns Hopkins University School of Medicine, Baltimore, United States

   Contribution

   PBR, Conception and design, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

10. Jenny Yu

    Rheumatology Division, Washington University School of Medicine, St. Louis, United States

    Contribution

    JY, Conception and design, Acquisition of data

    Competing interests

    The authors declare that no competing interests exist.

11. Joan K Riley

    Obstetrics and Gynecology Division, Washington University School of Medicine, St. Louis, United States

    Contribution

    JKR, Acquisition of data, Analysis and interpretation of data

    Competing interests

    The authors declare that no competing interests exist.

12. Jinfang Zhu

    Molecular and Cellular Immunoregulation Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States

    Contribution

    JZ, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The authors declare that no competing interests exist.

13. Zhigang Tian

    1. Department of Immunology, School of Life Sciences, University of Science and Technology China, Hefei, China
    2. Hefei National Laboratory for Physical Sciences at the Microscale, Hefei, China

    Contribution

    ZT, Conception and design, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    The authors declare that no competing interests exist.

14. Wayne M Yokoyama

    1. Rheumatology Division, Washington University School of Medicine, St. Louis, United States
    2. Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, United States

    Contribution

    WMY, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    yokoyama@dom.wustl.edu

    Competing interests

    The authors declare that no competing interests exist.

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