Dazed and Confused: NK Cells
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
Innate lymphoid cells (ILCs) are rapid producers of both proinflammatory and regulatory cytokines in response to local injury, inflammation, pathogen infection, or commensal microbiota perturbation (1). Because most ILCs have been shown to be tissue-resident during homeostasis (with the exception of circulating NK cells) in almost all organs analyzed, their ability to quickly respond to tissue stress and inflammation underpins their critical role in regulating tissue homeostasis and repair during infection or injury (2–4). Recent evidence has suggested that mature ILCs can be further classified into group 1, 2, and 3 ILCs based on different expression of transcription factors, cell surface markers, and effector cytokines (1). Mouse group 1 ILCs, which include natural killer (NK) cells and ILC1, were initially distinguished from other ILCs based on their constitutive expression of the transcription factor Tbx21 (T-bet), co-expression of activating receptors NKp46 and NK1.1, and production of interferon (IFN)-γ following activation (5). In humans, group 1 ILCs are harder to definitively differentiate from other ILCs due to the lack of lineage defining markers and reported functional plasticity amongst group 2 and group 3 ILCs (6).
ILC1 are recently discovered tissue-resident sentinels that function to protect the host from bacterial and viral pathogens at initial sites of infection (2, 7, 8). ILC1 rapidly produce IFN-γ following local dendritic cell activation and interleukin (IL)-12 production to limit viral replication and promote host survival before the recruitment of circulating lymphocytes into infected tissue (2). Unlike ILC1, NK cells can be recruited from the circulation into the parenchyma of infected or cancerous tissues where they display potent perforin-dependent cytotoxicity in addition to rapid IFN-γ production (9, 10). However, persistent inflammatory signals can also lead to unrestrained activation of group 1 ILCs during obesity and inflammatory bowel disease (IBD) (3, 11–14). While these studies suggest important roles for group 1 ILCs during host protection and pathology, gaps in evidence have inhibited the ability of recent studies to definitively distinguish between the roles of ILC1 and NK cells in these contexts.
Group 1 ILC Phenotypic and Functional Heterogeneity
NK cells, the founding member of ILCs, were initially defined based on the cell surface expression of NK1.1 in mouse or CD56 in human with the absence of cell surface expression of other lineage (Lin) defining markers including CD3, CD14, CD19, and TCR proteins (15). In subsequent mouse studies over the last 30 years, Lin−NK1.1+ cells were found to be heterogeneous for the expression of activating and inhibitory Ly49 receptors, cell surface integrins [α1β1 (CD49a), α2β1 (CD49b), αEβ7 (CD103)], cell surface proteins (TRAIL, CD69, CD27, CD11b), transcription factors (Eomes), chemokine receptors (CXCR6), and cytokine receptors (IL-7Rα) in various organs (1, 16). Similarly, human Lin−CD56+ cells have been reported to be heterogeneous for the expression of transcriptions factors (EOMES and T-BET), cell surface markers (CD49a, CD56, CD16, NKp80, CXCR6, IL-7Rα, CD94, CD69, NKp44), and cytotoxic molecules (Perforin) (1, 16). Early studies concluded that cells with an alternative cell surface or transcription factor phenotype from putative mature NK cells (mouse: Lin−NK1.1+T-bet+Eomes+CD49b+; human: Lin− IL-7Rα−CD56dimCD16+) in peripheral organs and blood likely represented immature NK (iNK) cells (17–21). This hypothesis is supported by studies demonstrating that subsets of developing mouse NK cells can be distinguished based on CD27 and CD11b expression (22, 23). Similarly, previous studies have suggested that CD56brightCD16− human NK cells in the blood may be immature precursors to CD56dimCD16+ mature NK cells (18, 19). However, whether other phenotypic differences observed in mouse and human group 1 ILCs are due to tissue-specific microenvironments, distinct lineages of cells, or developmental/activation states of NK cells is still under considerable debate and investigation.
Insight into these questions came shortly after the identification of Lin−IL-7Rα+ “helper” ILCs. Specifically, genetic evidence suggested that Tbx21-dependent IL-7Rα+Tbet+Eomes−NK1.1+NKp46+ “ILC1” in the small intestine did not require Eomes for their development, whereas NK cells did require Eomes (7). A recent study further supported these initial data by using Eomes-GFP reporter mice to generate core transcriptional signatures of Eomes− ILC1 and Eomes+ NK cells from 4 independent tissues. The identified core ILC1 signature led to the discovery of the inhibitory receptor CD200r1 as a stable marker expressed by ILC1 but not NK cells during homeostasis and inflammation (2). Additional lineage tracing experiments suggested that CD200r1+Eomes−CD49b− group 1 ILCs constituted a stable lineage during homeostasis, distinct from CD200r1-Eomes+CD49b+ mature NK (mNK) cells (2, 7, 24). Functional evidence suggestive of distinct group 1 ILCs in peripheral organs was supported by the findings that T-bet+Eomes−CD49b− group 1 ILCs (in addition to ILC2 and ILC3) were long-term tissue-resident cells, whereas Eomes+CD49b+ mNK cells were derived from the circulation in almost all organs tested in mouse parabiosis experiments (2, 4). Similarly, in one human study a subset of donor liver CXCR6+ group 1 ILCs was found to be maintained up to 13 years post-liver transplant while donor CXCR6− NK cells were absent, suggesting that a subset of long-term tissue-resident CXCR6+ group 1 ILCs are conserved in mammals (25). Furthermore, CD49b−Eomes− group 1 ILCs with a phenotype consistent with ILC1 in the liver express higher levels of TRAIL than mNK cells at steady state, and these ILC1 can produce higher levels of tumor necrosis factor (TNF)-α and IFN-γ following activation ex vivo (2, 17, 20, 24). While ILC1 in the small intestine were observed to have poor cytotoxicity and liver group 1 ILCs with a phenotype consistent with ILC1 express lower levels of granzymes A/B and perforin at steady state compared to NK cells (7, 24), peripheral ILC1 express higher transcript levels of granzyme C in addition to TRAIL and may kill target cells through alternative mechanisms (2, 24, 26–28). However, it will be important for future studies to determine whether perforin-independent killing mechanisms can be used as definitive criteria to functionally separate ILC1 from NK cells across all mouse and human tissues. Thus, significant phenotypic and functional heterogeneity has been demonstrated in group 1 ILCs; however, it is still unclear to what extent these individual pieces of evidence can be used in isolation to define group 1 ILC subsets.
Developmental and Activation States of Group 1 ILCs
Collective reports have demonstrated that iNK cells in mouse bone marrow and periphery can express Ly49 receptors, CD49a, CD90, TRAIL, CD69, and Eomes, and lack CD49b expression (3, 21, 29–31). Upon adoptive transfer into lymphopenic mice, iNK cells can induce CD49b expression and retain Eomes expression (3). During activation, mNK cells can induce expression of CD49a, CD69, TRAIL, and CD90 while also decreasing Eomes expression (2, 17, 29, 32), suggesting that iNK and mNK cell phenotypes can overlap with other reported group 1 ILC phenotypes based on these markers. Consistent with these findings, NK cells can repress Eomes expression and induce CD49a, TRAIL, and CD103 in response to TGFβ and IL-2 stimulation ex vivo (33, 34). These key findings make the current dogma of utilizing CD49a, CD49b, and Eomes expression in Lin−T-bet+NK1.1+NKp46+ cells insufficient to distinguish between group 1 ILC subsets and activation or developmental states of NK cells. Furthermore, adipose and small intestine iNK cells have also been found to be short-term (1 month), but not long term (4 months) tissue-resident in mouse parabiosis experiments (3), suggesting that short-term parabiosis (2 weeks-1 month) experiments are not sufficient to distinguish iNK cells from ILC1 without additional evidence. Thus, there is currently insufficient evidence to conclude that T-bet+ group 1 ILCs with the phenotype of CD49a+CD49b+Eomes+NK1.1+ are either tissue-resident NK (trNK) cells or transitional states of group 1 ILCs, because these cells may be activated NK cells in the tissue parenchyma following recruitment from circulation. Furthermore, CD49a+CD49b−Eomes+NK1.1+ cells may not represent a transitional subset of group 1 ILC, but instead may represent iNK cells in peripheral tissues, although further lineage tracing experiments will be necessary to clarify these issues in the field.
In the healthy state, mature human group 1 ILCs have been described to be heterogeneous for cell surface expression of CD56, CD16, and NKp80 in peripheral tissues (35). However, CD56 can be expressed on ILC progenitor populations and ILC3 in the tonsil (36), and may be downregulated during activation in a similar manner to CD16 and NKp80 (37–39). Thus, to date there are no known stable cell surface markers that can unequivocally distinguish between human mNK cells (or their developmental intermediates, which may be tissue-resident) and other proposed group 1 ILCs in inflamed human tissues, because activated mNK cells can lose expression of these cell surface markers during inflammation.
Mouse Group 1 ILC Development
Recent unbiased chromatin accessibility studies in mice suggest that NK cells can be defined epigenetically as a distinct ILC lineage through the enrichment of accessible T-bet and Eomes binding sites compared to other leukocytes (40). Similarly, mNK and iNK cells require Eomes for their development (2, 20, 41), suggesting that Eomes may be the master transcription factor that defines NK cell lineage identity in mice during homeostasis. In support of this hypothesis, mNK cells in the peritoneum, liver, spleen, salivary gland, and adipose tissue were all found to have a cell-intrinsic developmental requirement for Eomes and T-bet (2), arguing against tissue-specific transcription factor developmental requirements for mNK cells. While certain studies have observed that mNK cell numbers are normal in the absence of T-bet (7, 8, 42), it has been demonstrated previously that Tbx21−/− NK cells display an immature phenotype and are functionally deficient (3, 43–45). Therefore, because Tbx21 is required for optimal mature ILC1 and mNK development (2, 3, 46), Rag2−/− × Tbx21−/− mice are not a suitable model to test for the contributions of mature group 1 ILCs in vivo.
The transcription factors Id2 and Nfil3 have also been shown to be required for mature mouse ILC1 and NK cell development (47, 48). Certain studies have identified “tissue-resident NK cells,” “salivary gland ILCs,” and “type 1 ILCs” based on their development in the absence of Nfil3 (27, 33, 49). However, similar subsets have been also found to be Nfil3-dependent in a cell-intrinsic manner in other studies (2, 50). Because mNK cells can develop in an Nfil3-independent manner during virus-induced inflammation and aging (33, 51), analysis of Nfil3−/− mice is likely not sufficient to define group 1 ILC subsets due to these caveats. Previous studies have also utilized Zbtb16 fate-mapping studies and Id2 reporter mice to identify a common helper ILC precursor population that gives rise to all tissue-resident ILCs, but not mNK cells, to argue that ILC1 comprise a developmental lineage distinct from NK cells (7, 52, 53). However, a recent study using dual Zbtb16 and Id2 reporter mice demonstrated that both NK cells and ILC1 can develop from a Id2+Zbtb16+ shared precursor, suggesting that these transcription factors alone cannot be used to identify different group 1 ILC subsets during ontogeny (54). Instead, several studies have identified the transcription factor Zfp683 (Hobit) as highly expressed in peripheral ILC1 compared to mNK cells (2, 55, 56). Zfp683−/− mice display a loss of liver ILC1 but not other ILC populations (including ILC1 in other tissues) (2, 55), suggesting that mature liver ILC1 have a unique developmental pathway from other mouse ILCs. While developmental dependence on Eomes expression can be used to identify NK lineage cells in peripheral organs of mice, there is still no definitive evidence that a single transcription factor can define the development of other group 1 ILC subsets across all mouse tissues.
While collective evidence supports the hypothesis that mouse group 1 ILCs are composed of Eomes-dependent iNK and mNK cells, their activation or developmental states may be mistaken for novel subsets of group 1 ILCs. Eomes-independent ILC1 have been shown through single- cell sequencing, parabiosis, lineage tracing, and transcription factor deficient mouse experiments to be a distinct lineage of group 1 ILCs, and not a developmental or activation state of NK cells. In human tissues, there is currently no definitive evidence that can distinguish between developmental or activation states of group 1 ILCs during inflammation. Single cell sequencing studies will be needed to determine the extent of group 1 ILC heterogeneity in various peripheral tissues, and to identify stable markers that can distinguish between stable subsets of group 1 ILCs through lineage tracing in humanized mouse models.
The author confirms being the sole contributor of this work and has approved it for publication.
This work was supported by the National Institutes of Health (P30 DK063491 and AI145997 to TO'S).
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
With acknowledgments to Pennied Days by Night Moves.
2. Weizman OE, Adams NM, Schuster IS, Krishna C, Pritykin Y, Lau C, et al. ILC1 confer early host protection at initial sites of viral infection. Cell. (2017) 171:795–808.e12. doi: 10.1016/j.cell.2017.09.052
3. O'Sullivan TE, Rapp M, Fan X, Weizman OE, Bhardwaj P, Adams NM, et al. Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance. Immunity. (2016) 45:428–41. doi: 10.1016/j.immuni.2016.06.016
7. Klose CSN, Flach M, Möhle L, Rogell L, Hoyler T, Ebert K, et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell. (2014) 157:340–56. doi: 10.1016/j.cell.2014.03.030
8. Abt MC, Lewis BB, Caballero S, Xiong H, Carter RA, Sušac B, et al. Innate immune defenses mediated by two ILC subsets are critical for protection against acute clostridium difficile infection. Cell Host Microbe. (2015) 18:27–37. doi: 10.1016/j.chom.2015.06.011
11. Wensveen FM, Jelenčić V, Valentić S, Šestan M, Wensveen TT, Theurich S, et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat Immunol. (2015) 16:376–85. doi: 10.1038/ni.3120
12. Fuchs A, Vermi W, Lee JS, Lonardi S, Gilfillan S, Newberry RD, et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity. (2013) 38:769–81. doi: 10.1016/j.immuni.2013.02.010
13. Bernink JH, Peters CP, Munneke M, te Velde AA, Meijer SL, Weijer K, et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol. (2013) 14:221–9. doi: 10.1038/ni.2534
14. Vonarbourg C, Mortha A, Bui VL, Hernandez PP, Kiss EA, Hoyler T, et al. Regulated expression of nuclear receptor RORgammat confers distinct functional fates to NK cell receptor-expressing RORgammat(+) innate lymphocytes. Immunity. (2010) 33:736–51. doi: 10.1016/j.immuni.2010.10.017
17. Takeda K, Cretney E, Hayakawa Y, Ota T, Akiba H, Ogasawara K, et al. TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver. Blood. (2005) 105:2082–9. doi: 10.1182/blood-2004-08-3262
18. Romagnani C, Juelke K, Falco M, Morandi B, D'Agostino A, Costa R, et al. CD56brightCD16- killer Ig-like receptor- NK cells display longer telomeres and acquire features of CD56dim NK cells upon activation. J Immunol. (2007) 178:4947–55. doi: 10.4049/jimmunol.178.8.4947
19. Mace EM, Hsu AP, Monaco-Shawver L, Makedonas G, Rosen JB, Dropulic L, et al. Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56(bright) subset. Blood. (2013) 121:2669–77. doi: 10.1182/blood-2012-09-453969
20. Gordon SM, Chaix J, Rupp LJ, Wu J, Madera S, Sun JC, et al. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity. (2012) 36:55–67. doi: 10.1016/j.immuni.2011.11.016
24. Daussy C, Faure F, Mayol K, Viel S, Gasteiger G, Charrier E, et al. T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J Exp Med. (2014) 211:563–77. doi: 10.1084/jem.20131560
25. Cuff AO, Robertson FP, Stegmann KA, Pallett LJ, Maini MK, Davidson BR, et al. Eomeshi NK cells in human liver are long-lived and do not recirculate but can be replenished from the circulation. J Immunol. (2016) 197:4283–91. doi: 10.4049/jimmunol.1601424
26. Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med. (2001) 7:94–100. doi: 10.1038/83416
27. Dadi S, Chhangawala S, Whitlock BM, Franklin RA, Luo CT, Oh SA, et al. Cancer immunosurveillance by tissue-resident innate lymphoid cells and innate-like T cells. Cell. (2016) 164:365–77. doi: 10.1016/j.cell.2016.01.002
28. Boulenouar S, Michelet X, Duquette D, Alvarez D, Hogan AE, Dold C, et al. Adipose type one innate lymphoid cells regulate macrophage homeostasis through targeted cytotoxicity. Immunity. (2017) 46:273–86. doi: 10.1016/j.immuni.2017.01.008
29. Sheppard S, Schuster IS, Andoniou CE, Cocita C, Adejumo T, Kung SKP, et al. The murine natural cytotoxic receptor NKp46/NCR1 controls TRAIL protein expression in NK cells and ILC1s. Cell Rep. (2018) 22:3385–92. doi: 10.1016/j.celrep.2018.03.023
30. Kupz A, Scott TA, Belz GT, Andrews DM, Greyer M, Lew AM, et al. Contribution of Thy1+ NK cells to protective IFN-gamma production during Salmonella typhimurium infections. Proc Natl Acad Sci USA. (2013) 110:2252–7. doi: 10.1073/pnas.1222047110
31. Chaves P, Zriwil A, Wittmann L, Boukarabila H, Peitzsch C, Jacobsen SEW, et al. Loss of canonical notch signaling affects multiple steps in NK cell development in mice. J Immunol. (2018) 201:3307–19. doi: 10.4049/jimmunol.1701675
32. Bezman NA, Kim CC, Sun JC, Min-Oo G, Hendricks DW, Kamimura Y, et al. Molecular definition of the identity and activation of natural killer cells. Nat Immunol. (2012) 13:1000–9. doi: 10.1038/ni.2395
33. Cortez VS, Cervantes-Barragan L, Robinette ML, Bando JK, Wang Y, Geiger TL, et al. Transforming growth factor-beta signaling guides the differentiation of innate lymphoid cells in salivary glands. Immunity. (2016) 44:1127–39. doi: 10.1016/j.immuni.2016.03.007
34. Gao Y, Souza-Fonseca-Guimaraes F, Bald T, Ng SS, Young A, Ngiow SF, et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat Immunol. (2017) 18:1004–15. doi: 10.1038/ni.3800
35. Freud AG, Keller KA, Scoville SD, Mundy-Bosse BL, Cheng S, Youssef Y, et al. NKp80 defines a critical step during human natural killer cell development. Cell Rep. (2016) 16:379–91. doi: 10.1016/j.celrep.2016.05.095
36. Chen L, Youssef Y, Robinson C, Ernst GF, Carson MY, Young KA, et al. CD56 expression marks human group 2 innate lymphoid cell divergence from a shared NK cell and group 3 innate lymphoid cell developmental pathway. Immunity. (2018) 49:464–76.e4. doi: 10.1016/j.immuni.2018.08.010
37. Mavilio D, Lombardo G, Benjamin J, Kim D, Follman D, Marcenaro E, et al. Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci USA. (2005) 102:2886–91. doi: 10.1073/pnas.0409872102
38. Hu PF, Hultin LE, Hultin P, Hausner MA, Hirji K, Jewett A, et al. Natural killer cell immunodeficiency in HIV disease is manifest by profoundly decreased numbers of CD16+CD56+ cells and expansion of a population of CD16dimCD56- cells with low lytic activity. J Acquir Immune Defic Syndr Hum Retrovirol. (1995) 10:331–40. doi: 10.1097/00042560-199511000-00005
39. Klimosch SN, Bartel Y, Wiemann S, Steinle A. Genetically coupled receptor-ligand pair NKp80-AICL enables autonomous control of human NK cell responses. Blood. (2013) 122:2380–9. doi: 10.1182/blood-2013-01-479790
41. Pikovskaya O, Chaix J, Rothman NJ, Collins A, Chen YH, Scipioni AM, et al. Cutting edge: eomesodermin is sufficient to direct type 1 innate lymphocyte development into the conventional NK lineage. J Immunol. (2016) 196:1449–54. doi: 10.4049/jimmunol.1502396
42. Zhou J, Peng H, Li K, Qu K, Wang B, Wu Y, et al. Liver-resident NK cells control antiviral activity of hepatic T cells via the PD-1-PD-L1 axis. Immunity. (2019) 50:403–17.e4. doi: 10.1016/j.immuni.2018.12.024
43. Townsend MJ, Weinmann AS, Matsuda JL, Salomon R, Farnham PJ, Biron CA, et al. T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells. Immunity. (2004) 20:477–94. doi: 10.1016/S1074-7613(04)00076-7
44. Jenne CN, Enders A, Rivera R, Watson SR, Bankovich AJ, Pereira JP, et al. T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow. J Exp Med. (2009) 206:2469–81. doi: 10.1084/jem.20090525
45. Malaisé M, Rovira J, Renner P, Eggenhofer E, Sabet-Baktach M, Lantow M, et al. KLRG1+ NK cells protect T-bet-deficient mice from pulmonary metastatic colorectal carcinoma. J Immunol. (2014) 192:1954–61. doi: 10.4049/jimmunol.1300876
47. Geiger TL, Abt MC, Gasteiger G, Firth MA, O'Connor MH, Geary CD, et al. Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J Exp Med. (2014) 211:1723–31. doi: 10.1084/jem.20140212
48. Satoh-Takayama N, Lesjean-Pottier S, Vieira P, Sawa S, Eberl G, Vosshenrich CA, et al. IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors. J Exp Med. (2010) 207:273–80. doi: 10.1084/jem.20092029
49. Sojka DK, Plougastel-Douglas B, Yang L, Pak-Wittel MA, Artyomov MN, Ivanova Y, et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. Elife. (2014) 3:e01659. doi: 10.7554/eLife.01659
50. Erick TK, Anderson CK, Reilly EC, Wands JR, Brossay L. NFIL3 expression distinguishes tissue-resident NK cells and conventional NK-like cells in the mouse submandibular glands. J Immunol. (2016) 197:2485–91. doi: 10.4049/jimmunol.1601099
51. Firth MA, Madera S, Beaulieu AM, Gasteiger G, Castillo EF, Schluns KS, et al. Nfil3-independent lineage maintenance and antiviral response of natural killer cells. J Exp Med. (2013) 210:2981–90. doi: 10.1084/jem.20130417
52. Constantinides MG, Gudjonson H, McDonald BD, Ishizuka IE, Verhoef PA, Dinner AR, et al. PLZF expression maps the early stages of ILC1 lineage development. Proc Natl Acad Sci USA. (2015) 112:5123–8. doi: 10.1073/pnas.1423244112
54. Xu W, Cherrier DE, Chea S, Vosshenrich C, Serafini N, Petit M, et al. An Id2(RFP)-reporter mouse redefines innate lymphoid cell precursor potentials. Immunity. (2019) 50:1054–68.e3. doi: 10.1016/j.immuni.2019.02.022
55. Mackay LK, Minnich M, Kragten NA, Liao Y, Nota B, Seillet C, et al. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science. (2016) 352:459–63. doi: 10.1126/science.aad2035
56. Cortez VS, Ulland TK, Cervantes-Barragan L, Bando JK, Robinette ML, Wang Q, et al. SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-beta signaling. Nat Immunol. (2017) 18:995–1003. doi: 10.1038/ni.3809
Keywords: NK cells, group 1 ILCs, development, heterogeneity, ILC1
Citation: O'Sullivan TE (2019) Dazed and Confused: NK Cells. Front. Immunol. 10:2235. doi: 10.3389/fimmu.2019.02235
Received: 31 July 2019; Accepted: 04 September 2019;
Published: 20 September 2019.
Edited by:Emily Mace, Columbia University, United States
Reviewed by:Stephen Noel Waggoner, Cincinnati Children's Hospital Medical Center, United States
Copyright © 2019 O'Sullivan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Timothy E. O'Sullivan, firstname.lastname@example.org