Innate lymphoid cells (ILCs) are effectors and regulators of innate immunity and tissue modeling and repair. Researchers have identified subsets of ILCs with differing functional activities, capacities to produce cytokines and transcription factors required for development and function. Natural killer (NK) cells represent the prototypical member of the ILC family. Together with ILC1s, NK cells constitute group 1 ILCs, which are characterized by their capacity to produce interferon-γ and their functional dependence on the transcription factor T-bet. NK cells and ILC1s are developmentally distinct but share so many features that they are difficult to distinguish, particularly under conditions of infection and inflammation. Here we review current knowledge of NK cells and the various ILC1 subsets.
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Spits, H. & Di Santo, J.P. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat. Immunol. 12, 21–27 (2011).
Spits, H. et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).
Townsend, M.J. et al. T-bet regulates the terminal maturation and homeostasis of NK and Vα14i NKT cells. Immunity 20, 477–494 (2004).
Lanier, L.L., Phillips, J.H., Hackett, J. Jr., Tutt, M. & Kumar, V. Natural killer cells: definition of a cell type rather than a function. J. Immunol. 137, 2735–2739 (1986).
Lanier, L.L., Le, A.M., Civin, C.I., Loken, M.R. & Phillips, J.H. The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J. Immunol. 136, 4480–4486 (1986).
Nagler, A., Lanier, L.L., Cwirla, S. & Phillips, J.H. Comparative studies of human FcRIII-positive and negative natural killer cells. J. Immunol. 143, 3183–3191 (1989).
Cooper, M.A. et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset. Blood 97, 3146–3151 (2001).
Romagnani, C. et al. CD56brightCD16− killer Ig-like receptor− NK cells display longer telomeres and acquire features of CD56dim NK cells upon activation. J. Immunol. 178, 4947–4955 (2007).
Michel, T. et al. Human CD56bright NK cells: an update. J. Immunol. 196, 2923–2931 (2016).
Hu, P.F. 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. 10, 331–340 (1995).
Mavilio, D. 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 102, 2886–2891 (2005).
Milush, J.M. et al. CD56negCD16+ NK cells are activated mature NK cells with impaired effector function during HIV-1 infection. Retrovirology 10, 158 (2013).
Papewalis, C. et al. IFN-α skews monocytes into CD56+-expressing dendritic cells with potent functional activities in vitro and in vivo. J. Immunol. 180, 1462–1470 (2008).
Milush, J.M. et al. Functionally distinct subsets of human NK cells and monocyte/DC-like cells identified by coexpression of CD56, CD7, and CD4. Blood 114, 4823–4831 (2009).
Moffett, A. & Colucci, F. Uterine NK cells: active regulators at the maternal-fetal interface. J. Clin. Invest. 124, 1872–1879 (2014).
Doisne, J.M. et al. Composition, development, and function of uterine innate lymphoid cells. J. Immunol. 195, 3937–3945 (2015).
Kim, S. et al. In vivo developmental stages in murine natural killer cell maturation. Nat. Immunol. 3, 523–528 (2002).
Chiossone, L. et al. Maturation of mouse NK cells is a 4-stage developmental program. Blood 113, 5488–5496 (2009).
Peng, H. et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J. Clin. Invest. 123, 1444–1456 (2013).
Bezman, N.A. et al. Molecular definition of the identity and activation of natural killer cells. Nat. Immunol. 13, 1000–1009 (2012).
Arase, H., Saito, T., Phillips, J.H. & Lanier, L.L. Cutting edge: the mouse NK cell-associated antigen recognized by DX5 monoclonal antibody is CD49b (α2 integrin, very late antigen-2). J. Immunol. 167, 1141–1144 (2001).
Marquardt, N. et al. Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells. J. Immunol. 194, 2467–2471 (2015).
Bernink, J.H. et al. Interleukin-12 and -23 control plasticity of CD127+ group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity 43, 146–160 (2015).
Vosshenrich, C.A. et al. A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127. Nat. Immunol. 7, 1217–1224 (2006).
Daussy, C. 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. 211, 563–577 (2014).
Gordon, S.M. et al. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 36, 55–67 (2012).
Fathman, J.W. et al. Identification of the earliest natural killer cell-committed progenitor in murine bone marrow. Blood 118, 5439–5447 (2011).
Knox, J.J., Cosma, G.L., Betts, M.R. & McLane, L.M. Characterization of T-bet and eomes in peripheral human immune cells. Front. Immunol. 5, 217 (2014).
Gasteiger, G., Fan, X., Dikiy, S., Lee, S.Y. & Rudensky, A.Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science 350, 981–985 (2015).
Vonarbourg, C. et al. Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity 33, 736–751 (2010).
Klose, C.S. et al. A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells. Nature 494, 261–265 (2013).
Klose, C.S. et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157, 340–356 (2014).
Nielsen, N., Ødum, N., Ursø, B., Lanier, L.L. & Spee, P. Cytotoxicity of CD56bright NK cells towards autologous activated CD4+ T cells is mediated through NKG2D, LFA-1 and TRAIL and dampened via CD94/NKG2A. PLoS One 7, e31959 (2012).
Takeda, K. et al. TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver. Blood 105, 2082–2089 (2005).
Cortez, V.S., Fuchs, A., Cella, M., Gilfillan, S. & Colonna, M. Cutting edge: Salivary gland NK cells develop independently of Nfil3 in steady-state. J. Immunol. 192, 4487–4491 (2014).
Sojka, D.K. et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. eLife 3, e01659 (2014).
Firth, M.A. et al. Nfil3-independent lineage maintenance and antiviral response of natural killer cells. J. Exp. Med. 210, 2981–2990 (2013).
Dadi, S. et al. Cancer immunosurveillance by tissue-resident innate lymphoid cells and innate-like T cells. Cell 164, 365–377 (2016).
Robinette, M.L. et al. Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat. Immunol. 16, 306–317 (2015).
Bernink, J.H. et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol. 14, 221–229 (2013).
Fuchs, A. et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells. Immunity 38, 769–781 (2013).
Cepek, K.L. et al. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the αEβ7 integrin. Nature 372, 190–193 (1994).
Roan, F. et al. CD4+ Group 1 innate lymphoid cells (ILC) form a functionally distinct ILC subset that is increased in systemic sclerosis. J. Immunol. 196, 2051–2062 (2016).
Björklund, A.K. et al. The heterogeneity of human CD127+ innate lymphoid cells revealed by single-cell RNA sequencing. Nat. Immunol. 17, 451–460 (2016).
Zook, E.C. & Kee, B.L. Development of innate lymphoid cells. Nat. Immunol. 17, 775–782 (2016).
Yang, Q. et al. TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow. Nat. Immunol. 16, 1044–1050 (2015).
Constantinides, M.G., McDonald, B.D., Verhoef, P.A. & Bendelac, A. A committed precursor to innate lymphoid cells. Nature 508, 397–401 (2014).
Constantinides, M.G. et al. PLZF expression maps the early stages of ILC1 lineage development. Proc. Natl. Acad. Sci. USA 112, 5123–5128 (2015).
Renoux, V.M. et al. Identification of a human natural killer cell lineage-restricted progenitor in fetal and adult tissues. Immunity 43, 394–407 (2015).
Montaldo, E. et al. Human RORγt+CD34+ cells are lineage-specified progenitors of group 3 RORγt+ innate lymphoid cells. Immunity 41, 988–1000 (2014).
Crellin, N.K. et al. Regulation of cytokine secretion in human CD127+ LTi-like innate lymphoid cells by Toll-like receptor 2. Immunity 33, 752–764 (2010).
Crellin, N.K., Trifari, S., Kaplan, C.D., Cupedo, T. & Spits, H. Human NKp44+IL-22+ cells and LTi-like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells. J. Exp. Med. 207, 281–290 (2010).
Cella, M., Otero, K. & Colonna, M. Expansion of human NK-22 cells with IL-7, IL-2, and IL-1β reveals intrinsic functional plasticity. Proc. Natl. Acad. Sci. USA 107, 10961–10966 (2010).
Silver, J.S. et al. Inflammatory triggers associated with COPD exacerbations orchestrate ILC2 plasticity in the lung. Nat. Immunol. http://dx.doi.org/10.1038/ni.3443 (2016).
Ohne, Y. et al. IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity. Nat. Immunol. http://dx.doi.org/10.1038/ni.3447 (2016).
Lim, A.I. et al. IL-12 drives functional plasticity of human group 2 innate lymphoid cells. J. Exp. Med. 213, 569–583 (2016).
Bal, S.M. et al. Interleukin-1β, -4 and -12 control ILC2 fate in human airway inflammation. Nat. Immunol. 17, 636–645 (2016).
Peters, C.P., Mjösberg, J.M., Bernink, J.H. & Spits, H. Innate lymphoid cells in inflammatory bowel diseases. Immunol. Lett. 172, 124–131 (2016).
Jenne, C.N. et al. T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow. J. Exp. Med. 206, 2469–2481 (2009).
Abt, M.C. et al. Innate immune defenses mediated by two ILC subsets are critical for protection against acute Clostridium difficile infection. Cell Host Microbe 18, 27–37 (2015).
Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).
Powell, N. et al. The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity 37, 674–684 (2012).
Morvan, M.G. & Lanier, L.L. NK cells and cancer: you can teach innate cells new tricks. Nat. Rev. Cancer 16, 7–19 (2016).
Eisenring, M., vom Berg, J., Kristiansen, G., Saller, E. & Becher, B. IL-12 initiates tumor rejection via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46. Nat. Immunol. 11, 1030–1038 (2010).
H.S. is supported by an advanced European Research Council grant 341038. L.L. is an American Cancer Society Professor and is supported by US National Institutes of Health grant AI068129.
The authors declare no competing financial interests.
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Spits, H., Bernink, J. & Lanier, L. NK cells and type 1 innate lymphoid cells: partners in host defense. Nat Immunol 17, 758–764 (2016). https://doi.org/10.1038/ni.3482
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