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NK cells and type 1 innate lymphoid cells: partners in host defense

Nature Immunology volume 17, pages 758–764 (2016)Cite this article

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Abstract

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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Figure 1: Development of NK cells and ILCs under steady state conditions.
Figure 2: Plasticity of ILC2s and ILC3s.

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References

  1. 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).

    Article  CAS  PubMed  Google Scholar 

  2. Spits, H. et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Townsend, M.J. et al. T-bet regulates the terminal maturation and homeostasis of NK and Vα14i NKT cells. Immunity 20, 477–494 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    CAS  PubMed  Google Scholar 

  5. 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).

    CAS  PubMed  Google Scholar 

  6. 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).

    CAS  PubMed  Google Scholar 

  7. Cooper, M.A. et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset. Blood 97, 3146–3151 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. 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).

    Article  CAS  PubMed  Google Scholar 

  9. Michel, T. et al. Human CD56bright NK cells: an update. J. Immunol. 196, 2923–2931 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    CAS  PubMed  Google Scholar 

  11. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Moffett, A. & Colucci, F. Uterine NK cells: active regulators at the maternal-fetal interface. J. Clin. Invest. 124, 1872–1879 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Doisne, J.M. et al. Composition, development, and function of uterine innate lymphoid cells. J. Immunol. 195, 3937–3945 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kim, S. et al. In vivo developmental stages in murine natural killer cell maturation. Nat. Immunol. 3, 523–528 (2002).

    Article  PubMed  Google Scholar 

  18. Chiossone, L. et al. Maturation of mouse NK cells is a 4-stage developmental program. Blood 113, 5488–5496 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Peng, H. et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J. Clin. Invest. 123, 1444–1456 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bezman, N.A. et al. Molecular definition of the identity and activation of natural killer cells. Nat. Immunol. 13, 1000–1009 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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).

    Article  CAS  PubMed  Google Scholar 

  22. Marquardt, N. et al. Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells. J. Immunol. 194, 2467–2471 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. 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).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fathman, J.W. et al. Identification of the earliest natural killer cell-committed progenitor in murine bone marrow. Blood 118, 5439–5447 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  29. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    Article  CAS  PubMed  Google Scholar 

  32. 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).

    Article  CAS  PubMed  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Takeda, K. et al. TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver. Blood 105, 2082–2089 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. 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).

    Article  CAS  PubMed  Google Scholar 

  36. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Firth, M.A. et al. Nfil3-independent lineage maintenance and antiviral response of natural killer cells. J. Exp. Med. 210, 2981–2990 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dadi, S. et al. Cancer immunosurveillance by tissue-resident innate lymphoid cells and innate-like T cells. Cell 164, 365–377 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Robinette, M.L. et al. Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat. Immunol. 16, 306–317 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bernink, J.H. et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol. 14, 221–229 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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).

    Article  CAS  PubMed  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. 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).

    Article  PubMed  Google Scholar 

  45. Zook, E.C. & Kee, B.L. Development of innate lymphoid cells. Nat. Immunol. 17, 775–782 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Yang, Q. et al. TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow. Nat. Immunol. 16, 1044–1050 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Constantinides, M.G., McDonald, B.D., Verhoef, P.A. & Bendelac, A. A committed precursor to innate lymphoid cells. Nature 508, 397–401 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Constantinides, M.G. et al. PLZF expression maps the early stages of ILC1 lineage development. Proc. Natl. Acad. Sci. USA 112, 5123–5128 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. Montaldo, E. et al. Human RORγt+CD34+ cells are lineage-specified progenitors of group 3 RORγt+ innate lymphoid cells. Immunity 41, 988–1000 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. 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).

    Article  CAS  PubMed  Google Scholar 

  52. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

  55. 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).

  56. Lim, A.I. et al. IL-12 drives functional plasticity of human group 2 innate lymphoid cells. J. Exp. Med. 213, 569–583 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bal, S.M. et al. Interleukin-1β, -4 and -12 control ILC2 fate in human airway inflammation. Nat. Immunol. 17, 636–645 (2016).

    Article  CAS  PubMed  Google Scholar 

  58. Peters, C.P., Mjösberg, J.M., Bernink, J.H. & Spits, H. Innate lymphoid cells in inflammatory bowel diseases. Immunol. Lett. 172, 124–131 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Morvan, M.G. & Lanier, L.L. NK cells and cancer: you can teach innate cells new tricks. Nat. Rev. Cancer 16, 7–19 (2016).

    Article  CAS  PubMed  Google Scholar 

  64. 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).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Cell Biology, Academic Medical Center at the University of Amsterdam, Amsterdam, the Netherlands

    Hergen Spits & Jochem H Bernink

  2. Department of Experimental Immunology, Academic Medical Center at the University of Amsterdam, Amsterdam, the Netherlands

    Hergen Spits & Jochem H Bernink

  3. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA.,

    Lewis Lanier

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Correspondence to Hergen Spits.

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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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