Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Clonal expansion of innate and adaptive lymphocytes

Nature Reviews Immunology volume 20, pages 694–707 (2020)Cite this article

Subjects

Abstract

One of the hallmarks of the vertebrate adaptive immune system is the prolific expansion of individual cell clones that encounter their cognate antigen. More recently, however, there is growing evidence for the clonal expansion of innate lymphocytes, particularly in the context of pathogen challenge. Clonal expansion not only serves to amplify the number of specific lymphocytes to mount a robust protective response to the pathogen at hand but also results in selection and differentiation of the responding lymphocytes to generate a multitude of cell fates. Here, we summarize the evidence for clonal expansion in innate lymphocytes, which has primarily been observed in natural killer (NK) cells responding to cytomegalovirus infection, and consider the requirements for such a response in NK cells in light of those for T cells. Furthermore, we discuss multiple aspects of heterogeneity that both contribute to and result from the fundamental immunological process of clonal expansion, highlighting the parallels between innate and adaptive lymphocytes, with a particular focus on NK cells and CD8+ T cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Molecular mechanisms governing NK cell and CD8+ T cell clonal expansion.
Fig. 2: Processes that establish diversity in the naive lymphocyte pool.
Fig. 3: Processes resulting in differential selection of lymphocyte clones during infection.
Fig. 4: Models of lymphocyte differentiation during infection.

Similar content being viewed by others

References

  1. Zhang, Y. et al. Transposon molecular domestication and the evolution of the RAG recombinase. Nature 569, 79–84 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Schatz, D. G. & Ji, Y. Recombination centres and the orchestration of V(D)J recombination. Nat. Rev. Immunol. 11, 251–263 (2011).

    CAS  PubMed  Google Scholar 

  3. Pauling, L. A theory of the structure and process of formation of antibodies. J. Am. Chem. Soc. 62, 2643–2657 (1940).

    CAS  Google Scholar 

  4. Jerne, N. K. The natural-selection theory of antibody formation. Proc. Natl Acad. Sci. USA 41, 849–857 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Talmage, D. W. Allergy and immunology. Annu. Rev. Med. 8, 239–257 (1957).

    CAS  PubMed  Google Scholar 

  6. Burnet, F. M. The Clonal Selection Theory of Acquired Immunity (Vanderbilt Univ. Press, 1959). In this book, Burnet expands on his theory of clonal selection.

  7. Lau, C. M. & Sun, J. C. The widening spectrum of immunological memory. Curr. Opin. Immunol. 54, 42–49 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Sun, J. C., Beilke, J. N. & Lanier, L. L. Adaptive immune features of natural killer cells. Nature 457, 557–561 (2009). This landmark study shows NK cell memory specific to MCMV.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Badovinac, V. P., Haring, J. S. & Harty, J. T. Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8+ T cell response to infection. Immunity 26, 827–841 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Buchholz, V. R. et al. Disparate individual fates compose robust CD8+ T cell immunity. Science 340, 630–635 (2013).

    CAS  PubMed  Google Scholar 

  11. Gerlach, C. et al. Heterogeneous differentiation patterns of individual CD8+ T cells. Science 340, 635–639 (2013). Together with Buchholz et al. (2013), this seminal study demonstrates how robust CD8+ T cell responses comprise the heterogeneous individual outputs of single CD8+ T cells adhering to a common differentiation framework.

    CAS  PubMed  Google Scholar 

  12. Grassmann, S. et al. Distinct surface expression of activating receptor Ly49H drives differential expansion of NK cell clones upon murine cytomegalovirus infection. Immunity 50, 1391–1400 (2019). This study is the first to conclusively demonstrate and quantify the clonal nature of MCMV-driven NK cell expansion using single NK cell transfers.

    CAS  PubMed  Google Scholar 

  13. Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).

    CAS  PubMed  Google Scholar 

  14. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Lanier, L. L. NK cell recognition. Annu. Rev. Immunol. 23, 225–274 (2005).

    CAS  PubMed  Google Scholar 

  17. Brown, M. G. et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292, 934–937 (2001).

    CAS  PubMed  Google Scholar 

  18. Lee, S. H. et al. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nat. Genet. 28, 42–45 (2001).

    CAS  PubMed  Google Scholar 

  19. Scalzo, A. A., Fitzgerald, N. A., Simmons, A., La Vista, A. B. & Shellam, G. R. Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J. Exp. Med. 171, 1469–1483 (1990).

    CAS  PubMed  Google Scholar 

  20. Scalzo, A. A. et al. Genetic mapping of Cmv1 in the region of mouse chromosome 6 encoding the NK gene complex-associated loci Ly49 and musNKR-P1. Genomics 27, 435–441 (1995).

    CAS  PubMed  Google Scholar 

  21. Arase, H., Mocarski, E. S., Campbell, A. E., Hill, A. B. & Lanier, L. L. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326 (2002).

    CAS  PubMed  Google Scholar 

  22. Smith, H. R. et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl Acad. Sci. USA 99, 8826–8831 (2002). Together with Arase et al. (2002), this work identifies the MCMV-encoded glycoprotein m157 as the specific ligand for the activating receptor Ly49H.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Abi-Rached, L. & Parham, P. Natural selection drives recurrent formation of activating killer cell immunoglobulin-like receptor and Ly49 from inhibitory homologues. J. Exp. Med. 201, 1319–1332 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Daniels, K. A. et al. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J. Exp. Med. 194, 29–44 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Dokun, A. O. et al. Specific and nonspecific NK cell activation during virus infection. Nat. Immunol. 2, 951–956 (2001). Together with Daniels et al. (2001), this study is the first to describe clonal-like expansion of a population of NK cells expressing the activating receptor Ly49H in response to MCMV infection.

    CAS  PubMed  Google Scholar 

  26. Beaulieu, A. M. & Sun, J. C. Tracking effector and memory NK cells during MCMV infection. Methods Mol. Biol. 1441, 1–12 (2016).

    CAS  PubMed  Google Scholar 

  27. Cooper, M. A. et al. Cytokine-induced memory-like natural killer cells. Proc. Natl Acad. Sci. USA 106, 1915–1919 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Sun, J. C., Beilke, J. N., Bezman, N. A. & Lanier, L. L. Homeostatic proliferation generates long-lived natural killer cells that respond against viral infection. J. Exp. Med. 208, 357–368 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. O’Leary, J. G., Goodarzi, M., Drayton, D. L. & von Andrian, U. H. T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat. Immunol. 7, 507–516 (2006).

    PubMed  Google Scholar 

  30. Paust, S. et al. Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat. Immunol. 11, 1127–1135 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Hammer, Q., Ruckert, T. & Romagnani, C. Natural killer cell specificity for viral infections. Nat. Immunol. 19, 800–808 (2018).

    CAS  PubMed  Google Scholar 

  32. Gumá, M. et al. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 104, 3664–3671 (2004). This key study describes the enrichment of human NKG2C+ NK cells in the context of HCMV infection.

    PubMed  Google Scholar 

  33. Guma, M. et al. Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood 107, 3624–3631 (2006).

    CAS  PubMed  Google Scholar 

  34. Lopez-Vergès, S. et al. Expansion of a unique CD57+NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc. Natl Acad. Sci. USA 108, 14725–14732 (2011).

    PubMed  PubMed Central  Google Scholar 

  35. Hendricks, D. W. et al. Cutting edge: NKG2ChiCD57+ NK cells respond specifically to acute infection with cytomegalovirus and not Epstein–Barr virus. J. Immunol. 192, 4492–4496 (2014).

    CAS  PubMed  Google Scholar 

  36. Hammer, Q. et al. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat. Immunol. 19, 453–463 (2018). This key study describes the ligand that drives expansion of NKG2C+ NK cells during HCMV infection.

    CAS  PubMed  Google Scholar 

  37. Beziat, V. et al. NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood 121, 2678–2688 (2013). This study reports that HCMV infection imprints the KIR repertoire of human NK cells, a process that is probably shaped by clonal-like expansion.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Naiyer, M. M. et al. KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA−C. Sci. Immunol. 2, aal5296 (2017).

    Google Scholar 

  39. Reeves, R. K. et al. Antigen-specific NK cell memory in rhesus macaques. Nat. Immunol. 16, 927–932 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Weizman, O. E. et al. Mouse cytomegalovirus-experienced ILC1s acquire a memory response dependent on the viral glycoprotein m12. Nat. Immunol. 20, 1004–1011 (2019). This study is the first to describe expansion of ILC1s to the viral pathogen MCMV.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Martinez-Gonzalez, I. et al. Allergen-experienced group 2 innate lymphoid cells acquire memory-like properties and enhance allergic lung inflammation. Immunity 45, 198–208 (2016).

    CAS  PubMed  Google Scholar 

  42. Aguilar, O. A. et al. A viral immunoevasin controls innate immunity by targeting the prototypical natural killer cell receptor family. Cell 169, 58–71 (2017).

    CAS  PubMed  Google Scholar 

  43. Sun, J. C. & Lanier, L. L. The natural selection of herpesviruses and virus-specific NK cell receptors. Viruses 1, 362 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Mercado, R. et al. Early programming of T cell populations responding to bacterial infection. J. Immunol. 165, 6833–6839 (2000).

    CAS  PubMed  Google Scholar 

  45. Kaech, S. M. & Ahmed, R. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells. Nat. Immunol. 2, 415–422 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. van Stipdonk, M. J., Lemmens, E. E. & Schoenberger, S. P. Naïve CTLs require a single brief period of antigen stimulation for clonal expansion and differentiation. Nat. Immunol. 2, 423–429 (2001).

    PubMed  Google Scholar 

  47. Prlic, M., Hernandez-Hoyos, G. & Bevan, M. J. Duration of the initial TCR stimulus controls the magnitude but not functionality of the CD8+ T cell response. J. Exp. Med. 203, 2135–2143 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Tewari, K., Walent, J., Svaren, J., Zamoyska, R. & Suresh, M. Differential requirement for Lck during primary and memory CD8+ T cell responses. Proc. Natl Acad. Sci. USA 103, 16388–16393 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Zehn, D., Lee, S. Y. & Bevan, M. J. Complete but curtailed T-cell response to very low-affinity antigen. Nature 458, 211–214 (2009). This key study investigates how antigen affinity influences the expansion of CD8+ T cells during pathogen challenge.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Williams, M. A. & Bevan, M. J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007).

    CAS  PubMed  Google Scholar 

  51. O’Sullivan, T. E., Sun, J. C. & Lanier, L. L. Natural killer cell memory. Immunity 43, 634–645 (2015).

    PubMed  PubMed Central  Google Scholar 

  52. Sharpe, A. H. & Freeman, G. J. The B7–CD28 superfamily. Nat. Rev. Immunol. 2, 116–126 (2002).

    CAS  PubMed  Google Scholar 

  53. Tan, J. T., Whitmire, J. K., Ahmed, R., Pearson, T. C. & Larsen, C. P. 4-1BB ligand, a member of the TNF family, is important for the generation of antiviral CD8 T cell responses. J. Immunol. 163, 4859–4868 (1999).

    CAS  PubMed  Google Scholar 

  54. Tan, J. T. et al. 4-1BB costimulation is required for protective anti-viral immunity after peptide vaccination. J. Immunol. 164, 2320–2325 (2000).

    CAS  PubMed  Google Scholar 

  55. Nandi, D., Gross, J. A. & Allison, J. P. CD28-mediated costimulation is necessary for optimal proliferation of murine NK cells. J. Immunol. 152, 3361–3369 (1994).

    CAS  PubMed  Google Scholar 

  56. Galea-Lauri, J. et al. Expression of a variant of CD28 on a subpopulation of human NK cells: implications for B7-mediated stimulation of NK cells. J. Immunol. 163, 62–70 (1999).

    CAS  PubMed  Google Scholar 

  57. Goodier, M. R. & Londei, M. CD28 is not directly involved in the response of human CD3–CD56+ natural killer cells to lipopolysaccharide: a role for T cells. Immunology 111, 384–390 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Nabekura, T. et al. Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection. Immunity 40, 225–234 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Nabekura, T. et al. Cutting edge: NKG2D signaling enhances NK cell responses but alone is insufficient to drive expansion during mouse cytomegalovirus infection. J. Immunol. 199, 1567–1571 (2017).

    CAS  PubMed  Google Scholar 

  60. Nabekura, T. & Lanier, L. L. Activating receptors for self-MHC class I enhance effector functions and memory differentiation of NK cells during mouse cytomegalovirus infection. Immunity 45, 74–82 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Curtsinger, J. M. & Mescher, M. F. Inflammatory cytokines as a third signal for T cell activation. Curr. Opin. Immunol. 22, 333–340 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Le Bon, A. et al. Direct stimulation of T cells by type I IFN enhances the CD8+ T cell response during cross-priming. J. Immunol. 176, 4682–4689 (2006).

    PubMed  Google Scholar 

  63. Schmidt, C. S. & Mescher, M. F. Adjuvant effect of IL-12: conversion of peptide antigen administration from tolerizing to immunizing for CD8+ T cells in vivo. J. Immunol. 163, 2561–2567 (1999).

    CAS  PubMed  Google Scholar 

  64. Aichele, P. et al. CD8 T cells specific for lymphocytic choriomeningitis virus require type I IFN receptor for clonal expansion. J. Immunol. 176, 4525–4529 (2006).

    CAS  PubMed  Google Scholar 

  65. Kolumam, G. A., Thomas, S., Thompson, L. J., Sprent, J. & Murali-Krishna, K. Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J. Exp. Med. 202, 637–650 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Keppler, S. J., Theil, K., Vucikuja, S. & Aichele, P. Effector T-cell differentiation during viral and bacterial infections: role of direct IL-12 signals for cell fate decision of CD8+ T cells. Eur. J. Immunol. 39, 1774–1783 (2009).

    CAS  PubMed  Google Scholar 

  67. Xiao, Z., Casey, K. A., Jameson, S. C., Curtsinger, J. M. & Mescher, M. F. Programming for CD8 T cell memory development requires IL-12 or type I IFN. J. Immunol. 182, 2786–2794 (2009).

    CAS  PubMed  Google Scholar 

  68. Pearce, E. L. & Shen, H. Generation of CD8 T cell memory is regulated by IL-12. J. Immunol. 179, 2074–2081 (2007).

    CAS  PubMed  Google Scholar 

  69. Joshi, N. S. et al. Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor. Immunity 27, 281–295 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Pipkin, M. E. et al. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32, 79–90 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Geary, C. D. et al. Non-redundant ISGF3 components promote NK cell survival in an auto-regulatory manner during viral infection. Cell Rep. 24, 1949–1957.e6 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Madera, S. et al. Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide. J. Exp. Med. 213, 225–233 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Sun, J. C. et al. Proinflammatory cytokine signaling required for the generation of natural klller cell memory. J. Exp. Med. 209, 947–954 (2012). This report is the first to elucidate a key requirement for pro-inflammatory cytokines in NK cell clonal expansion.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Crouse, J. et al. Type I interferons protect T cells against NK cell attack mediated by the activating receptor NCR1. Immunity 40, 961–973 (2014).

    CAS  PubMed  Google Scholar 

  75. Xu, H. C. et al. Type I interferon protects antiviral CD8+ T cells from NK cell cytotoxicity. Immunity 40, 949–960 (2014).

    CAS  PubMed  Google Scholar 

  76. Nabekura, T., Girard, J. P. & Lanier, L. L. IL-33 receptor ST2 amplifies the expansion of NK cells and enhances host defense during mouse cytomegalovirus infection. J. Immunol. 194, 5948–5952 (2015).

    CAS  PubMed  Google Scholar 

  77. Bonilla, W. V. et al. The alarmin interleukin-33 drives protective antiviral CD8+ T cell responses. Science 335, 984–989 (2012).

    CAS  PubMed  Google Scholar 

  78. Madera, S. & Sun, J. C. Cutting edge: stage-specific requirement of IL-18 for antiviral NK cell expansion. J. Immunol. 194, 1408–1412 (2015).

    CAS  PubMed  Google Scholar 

  79. Haring, J. S. & Harty, J. T. Interleukin-18-related genes are induced during the contraction phase but do not play major roles in regulating the dynamics or function of the T-cell response to Listeria monocytogenes infection. Infect. Immun. 77, 1894–1903 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Rolle, A. et al. IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion. J. Clin. Invest. 124, 5305–5316 (2014).

    PubMed  PubMed Central  Google Scholar 

  81. Luetke-Eversloh, M. et al. Human cytomegalovirus drives epigenetic imprinting of the IFNG locus in NKG2Chi natural killer cells. PLOS Pathog. 10, e1004441 (2014).

    PubMed  PubMed Central  Google Scholar 

  82. Lam, V. C., Folkersen, L., Aguilar, O. A. & Lanier, L. L. KLF12 regulates mouse NK cell proliferation. J. Immunol. 203, 981–989 (2019).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Huntington, N. D. et al. Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nat. Immunol. 8, 856–863 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Rubinstein, M. P. et al. IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response. Blood 112, 3704–3712 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Yajima, T. et al. IL-15 regulates CD8+ T cell contraction during primary infection. J. Immunol. 176, 507–515 (2006).

    CAS  PubMed  Google Scholar 

  87. Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Intlekofer, A. M. et al. Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science 321, 408–411 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Banerjee, A. et al. Cutting edge: the transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche. J. Immunol. 185, 4988–4992 (2010).

    CAS  PubMed  Google Scholar 

  90. Sullivan, B. M., Juedes, A., Szabo, S. J., von Herrath, M. & Glimcher, L. H. Antigen-driven effector CD8 T cell function regulated by T-bet. Proc. Natl Acad. Sci. USA 100, 15818–15823 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Intlekofer, A. M. et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat. Immunol. 6, 1236–1244 (2005).

    CAS  PubMed  Google Scholar 

  92. Madera, S. et al. Cutting edge: divergent requirement of T-box transcription factors in effector and memory NK cells. J. Immunol. 200, 1977–1981 (2018).

    CAS  PubMed  Google Scholar 

  93. Adams, N. M. et al. Transcription factor IRF8 orchestrates the adaptive natural killer cell response. Immunity 48, 1172–1182.e6 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Beaulieu, A. M., Zawislak, C. L., Nakayama, T. & Sun, J. C. The transcription factor Zbtb32 controls the proliferative burst of virus-specific natural killer cells responding to infection. Nat. Immunol. 15, 546–553 (2014). This report is the first to identify a key transcriptional regulator of antiviral NK cell clonal expansion.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Rapp, M. et al. Core-binding factor β and Runx transcription factors promote adaptive natural killer cell responses. Sci. Immunol. 2, aan3796 (2017).

    Google Scholar 

  96. Shin, H. M. et al. Transient expression of ZBTB32 in anti-viral CD8+ T cells limits the magnitude of the effector response and the generation of memory. PLOS Pathog. 13, e1006544 (2017).

    PubMed  PubMed Central  Google Scholar 

  97. Miyagawa, F. et al. Interferon regulatory factor 8 integrates T-cell receptor and cytokine-signaling pathways and drives effector differentiation of CD8 T cells. Proc. Natl Acad. Sci. USA 109, 12123–12128 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Sun, L. et al. Interferon regulator factor 8 (IRF8) limits ocular pathology during HSV-1 infection by restraining the activation and expansion of CD8+ T cells. PLoS ONE 11, e0155420 (2016).

    PubMed  PubMed Central  Google Scholar 

  99. Nayar, R. et al. Graded levels of IRF4 regulate CD8+ T cell differentiation and expansion, but not attrition, in response to acute virus infection. J. Immunol. 192, 5881–5893 (2014).

    CAS  PubMed  Google Scholar 

  100. Yao, S. et al. Interferon regulatory factor 4 sustains CD8+ T cell expansion and effector differentiation. Immunity 39, 833–845 (2013).

    CAS  PubMed  Google Scholar 

  101. Man, K. et al. The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat. Immunol. 14, 1155–1165 (2013).

    CAS  PubMed  Google Scholar 

  102. Raczkowski, F. et al. The transcription factor interferon regulatory factor 4 is required for the generation of protective effector CD8+ T cells. Proc. Natl Acad. Sci. USA 110, 15019–15024 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Cannarile, M. A. et al. Transcriptional regulator Id2 mediates CD8+ T cell immunity. Nat. Immunol. 7, 1317–1325 (2006).

    CAS  PubMed  Google Scholar 

  104. Yang, C. Y. et al. The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets. Nat. Immunol. 12, 1221–1229 (2011).

    CAS  PubMed  Google Scholar 

  105. Zook, E. C. et al. Transcription factor ID2 prevents E proteins from enforcing a naive T lymphocyte gene program during NK cell development. Sci. Immunol. 3 (2018).

  106. Ji, Y. et al. Repression of the DNA-binding inhibitor Id3 by Blimp-1 limits the formation of memory CD8+ T cells. Nat. Immunol. 12, 1230–1237 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Lau, C. M. et al. Epigenetic control of innate and adaptive immune memory. Nat. Immunol. 19, 963–972 (2018). This key study compares the transcriptome and epigenome of NK cells and CD8+ T cells in the same host as they undergo clonal expansion to generate memory against CMV infection, and identifies a common epigenetic signature between innate and adaptive lymphocytes.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Schlums, H. et al. Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42, 443–456 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Lee, J. et al. Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals. Immunity 42, 431–442 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Burnet, F. M. A modification of Jerne’s theory of antibody production using the concept of clonal selection. Austr. J. Sci. 20, 67–69 (1957).

    Google Scholar 

  111. Davis, M. M. & Bjorkman, P. J. T-cell antigen receptor genes and T-cell recognition. Nature 334, 395–402 (1988).

    CAS  PubMed  Google Scholar 

  112. Casrouge, A. et al. Size estimate of the αβ TCR repertoire of naive mouse splenocytes. J. Immunol. 164, 5782–5787 (2000).

    CAS  PubMed  Google Scholar 

  113. Kedzierska, K. et al. Quantification of repertoire diversity of influenza-specific epitopes with predominant public or private TCR usage. J. Immunol. 177, 6705–6712 (2006).

    CAS  PubMed  Google Scholar 

  114. Malherbe, L., Hausl, C., Teyton, L. & McHeyzer-Williams, M. G. Clonal selection of helper T cells is determined by an affinity threshold with no further skewing of TCR binding properties. Immunity 21, 669–679 (2004).

    CAS  PubMed  Google Scholar 

  115. Maryanski, J. L., Jongeneel, C. V., Bucher, P., Casanova, J. L. & Walker, P. R. Single-cell PCR analysis of TCR repertoires selected by antigen in vivo: a high magnitude CD8 response is comprised of very few clones. Immunity 4, 47–55 (1996).

    CAS  PubMed  Google Scholar 

  116. Jenkins, M. K., Chu, H. H., McLachlan, J. B. & Moon, J. J. On the composition of the preimmune repertoire of T cells specific for peptide–major histocompatibility complex ligands. Annu. Rev. Immunol. 28, 275–294 (2010).

    CAS  PubMed  Google Scholar 

  117. Arstila, T. P. et al. A direct estimate of the human αβ T cell receptor diversity. Science 286, 958–961 (1999).

    CAS  PubMed  Google Scholar 

  118. Das, J. & Khakoo, S. I. NK cells: tuned by peptide? Immunol. Rev. 267, 214–227 (2015).

    CAS  PubMed  Google Scholar 

  119. Saleh, A. et al. Identification of probabilistic transcriptional switches in the Ly49 gene cluster: a eukaryotic mechanism for selective gene activation. Immunity 21, 55–66 (2004).

    CAS  PubMed  Google Scholar 

  120. Horowitz, A. et al. Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry. Sci. Transl Med. 5, 208ra145 (2013).

    PubMed  PubMed Central  Google Scholar 

  121. Wu, C. et al. Clonal expansion and compartmentalized maintenance of rhesus macaque NK cell subsets. Sci. Immunol. 3, eaat9781 (2018).

    PubMed  PubMed Central  Google Scholar 

  122. Adams, N. M. et al. Cytomegalovirus infection drives avidity selection of natural killer cells. Immunity 50, 1381–1390.e5 (2019). This study demonstrates the selection of naive NK cells during MCMV infection on the basis of their avidity, which is analogous to clonal selection of adaptive lymphocytes.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).

    CAS  PubMed  Google Scholar 

  124. Nemazee, D. Mechanisms of central tolerance for B cells. Nat. Rev. Immunol. 17, 281–294 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Anfossi, N. et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity 25, 331–342 (2006).

    CAS  PubMed  Google Scholar 

  126. Johansson, S. et al. Natural killer cell education in mice with single or multiple major histocompatibility complex class I molecules. J. Exp. Med. 201, 1145–1155 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Kim, S. et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436, 709–713 (2005). This key study describes how inhibitory receptor–MHC class I interactions influence the development and functional responsiveness of NK cells.

    CAS  PubMed  Google Scholar 

  128. Elliott, J. M., Wahle, J. A. & Yokoyama, W. M. MHC class I-deficient natural killer cells acquire a licensed phenotype after transfer into an MHC class I-sufficient environment. J. Exp. Med. 207, 2073–2079 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Joncker, N. T., Shifrin, N., Delebecque, F. & Raulet, D. H. Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment. J. Exp. Med. 207, 2065–2072 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Brodin, P., Lakshmikanth, T., Johansson, S., Karre, K. & Hoglund, P. The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells. Blood 113, 2434–2441 (2009).

    CAS  PubMed  Google Scholar 

  131. Joncker, N. T., Fernandez, N. C., Treiner, E., Vivier, E. & Raulet, D. H. NK cell responsiveness is tuned commensurate with the number of inhibitory receptors for self-MHC class I: the rheostat model. J. Immunol. 182, 4572–4580 (2009).

    CAS  PubMed  Google Scholar 

  132. Yu, J. et al. Hierarchy of the human natural killer cell response is determined by class and quantity of inhibitory receptors for self-HLA-B and HLA-C ligands. J. Immunol. 179, 5977–5989 (2007).

    CAS  PubMed  Google Scholar 

  133. Ogasawara, K., Benjamin, J., Takaki, R., Phillips, J. H. & Lanier, L. L. Function of NKG2D in natural killer cell-mediated rejection of mouse bone marrow grafts. Nat. Immunol. 6, 938–945 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Oppenheim, D. E. et al. Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Nat. Immunol. 6, 928–937 (2005).

    CAS  PubMed  Google Scholar 

  135. Sun, J. C. & Lanier, L. L. Tolerance of NK cells encountering their viral ligand during development. J. Exp. Med. 205, 1819–1828 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Tripathy, S. K. et al. Continuous engagement of a self-specific activation receptor induces NK cell tolerance. J. Exp. Med. 205, 1829–1841 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Sun, J. C. & Lanier, L. L. Cutting edge: viral infection breaks NK cell tolerance to ‘missing self’. J. Immunol. 181, 7453–7457 (2008).

    CAS  PubMed  Google Scholar 

  138. Orr, M. T., Murphy, W. J. & Lanier, L. L. ‘Unlicensed’ natural killer cells dominate the response to cytomegalovirus infection. Nat. Immunol. 11, 321–327 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Fink, P. J. & Hendricks, D. W. Post-thymic maturation: young T cells assert their individuality. Nat. Rev. Immunol. 11, 544–549 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Boursalian, T. E., Golob, J., Soper, D. M., Cooper, C. J. & Fink, P. J. Continued maturation of thymic emigrants in the periphery. Nat. Immunol. 5, 418–425 (2004).

    CAS  PubMed  Google Scholar 

  141. Hendricks, D. W. & Fink, P. J. Recent thymic emigrants are biased against the T-helper type 1 and toward the T-helper type 2 effector lineage. Blood 117, 1239–1249 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Makaroff, L. E., Hendricks, D. W., Niec, R. E. & Fink, P. J. Postthymic maturation influences the CD8 T cell response to antigen. Proc. Natl Acad. Sci. USA 106, 4799–4804 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Priyadharshini, B., Welsh, R. M., Greiner, D. L., Gerstein, R. M. & Brehm, M. A. Maturation-dependent licensing of naive T cells for rapid TNF production. PLoS ONE 5, e15038 (2010).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  145. Hayakawa, Y. & Smyth, M. J. CD27 dissects mature NK cells into two subsets with distinct responsiveness and migratory capacity. J. Immunol. 176, 1517–1524 (2006).

    CAS  PubMed  Google Scholar 

  146. Huntington, N. D. et al. NK cell maturation and peripheral homeostasis is associated with KLRG1 up-regulation. J. Immunol. 178, 4764–4770 (2007).

    CAS  PubMed  Google Scholar 

  147. Caligiuri, M. A. Human natural killer cells. Blood 112, 461–469 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Crinier, A. et al. High-dimensional single-cell analysis identifies organ-specific signatures and conserved NK cell subsets in humans and mice. Immunity 49, 971–986.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. van Heijst, J. W. et al. Recruitment of antigen-specific CD8+ T cells in response to infection is markedly efficient. Science 325, 1265–1269 (2009). This key study quantifies the efficiency by which T cells are recruited to the site of infection and recognize cognate antigen to drive clonal expansion.

    PubMed  Google Scholar 

  150. McHeyzer-Williams, M. G. & Davis, M. M. Antigen-specific development of primary and memory T cells in vivo. Science 268, 106–111 (1995).

    CAS  PubMed  Google Scholar 

  151. Cho, Y. L. et al. TCR signal quality modulates fate decisions of single CD4+ T cells in a probabilistic manner. Cell Rep. 20, 806–818 (2017).

    CAS  PubMed  Google Scholar 

  152. Busch, D. H. & Pamer, E. G. T cell affinity maturation by selective expansion during infection. J. Exp. Med. 189, 701–710 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Savage, P. A., Boniface, J. J. & Davis, M. M. A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity 10, 485–492 (1999). Together with Busch and Pamer (1999), this early study describes how clonal expansion selects for a T cell repertoire containing higher affinity clones, particularly during secondary responses.

    CAS  PubMed  Google Scholar 

  154. Heinzel, S. et al. A Myc-dependent division timer complements a cell-death timer to regulate T cell and B cell responses. Nat. Immunol. 18, 96–103 (2017).

    CAS  PubMed  Google Scholar 

  155. Langenkamp, A. et al. T cell priming by dendritic cells: thresholds for proliferation, differentiation and death and intraclonal functional diversification. Eur. J. Immunol. 32, 2046–2054 (2002).

    CAS  PubMed  Google Scholar 

  156. Alexander-Miller, M. A., Leggatt, G. R., Sarin, A. & Berzofsky, J. A. Role of antigen, CD8, and cytotoxic T lymphocyte (CTL) avidity in high dose antigen induction of apoptosis of effector CTL. J. Exp. Med. 184, 485–492 (1996).

    CAS  PubMed  Google Scholar 

  157. Critchfield, J. M. et al. T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science 263, 1139–1143 (1994).

    CAS  PubMed  Google Scholar 

  158. Lichterfeld, M. et al. Selective depletion of high-avidity human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells after early HIV-1 infection. J. Virol. 81, 4199–4214 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Tripathy, S. K., Smith, H. R., Holroyd, E. A., Pingel, J. T. & Yokoyama, W. M. Expression of m157, a murine cytomegalovirus-encoded putative major histocompatibility class I (MHC-I)-like protein, is independent of viral regulation of host MHC-I. J. Virol. 80, 545–550 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. McNally, J. M. et al. Attrition of bystander CD8 T cells during virus-induced T-cell and interferon responses. J. Virol. 75, 5965–5976 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Selin, L. K. et al. Attrition of T cell memory: selective loss of LCMV epitope-specific memory CD8 T cells following infections with heterologous viruses. Immunity 11, 733–742 (1999).

    CAS  PubMed  Google Scholar 

  162. Welsh, R. M. & Selin, L. K. Attrition of memory CD8 T cells. Nature 459, E3–E4 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Kedl, R. M. et al. T cells compete for access to antigen-bearing antigen-presenting cells. J. Exp. Med. 192, 1105–1113 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Willis, R. A., Kappler, J. W. & Marrack, P. C. CD8 T cell competition for dendritic cells in vivo is an early event in activation. Proc. Natl Acad. Sci. USA 103, 12063–12068 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Johnson, L. R., Weizman, O. E., Rapp, M., Way, S. S. & Sun, J. C. Epitope-specific vaccination limits clonal expansion of heterologous naive T cells during viral challenge. Cell Rep. 17, 636–644 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Oberle, S. G. et al. A minimum epitope overlap between infections strongly narrows the emerging T cell repertoire. Cell Rep. 17, 627–635 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Selin, L. K. et al. CD8 memory T cells: cross-reactivity and heterologous immunity. Semin. Immunol. 16, 335–347 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Muschaweckh, A. et al. Antigen-dependent competition shapes the local repertoire of tissue-resident memory CD8+ T cells. J. Exp. Med. 213, 3075–3086 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Zaid, A. et al. Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl Acad. Sci. USA 111, 5307–5312 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Kamimura, Y. & Lanier, L. L. Homeostatic control of memory cell progenitors in the natural killer cell lineage. Cell Rep. 10, 280–291 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Kaech, S. M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 4, 1191–1198 (2003).

    CAS  PubMed  Google Scholar 

  172. Reiner, S. L., Sallusto, F. & Lanzavecchia, A. Division of labor with a workforce of one: challenges in specifying effector and memory T cell fate. Science 317, 622–625 (2007).

    CAS  PubMed  Google Scholar 

  173. Gerlach, C. et al. One naive T cell, multiple fates in CD8+ T cell differentiation. J. Exp. Med. 207, 1235–1246 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Stemberger, C. et al. A single naive CD8+ T cell precursor can develop into diverse effector and memory subsets. Immunity 27, 985–997 (2007).

    CAS  PubMed  Google Scholar 

  175. Opferman, J. T., Ober, B. T. & Ashton-Rickardt, P. G. Linear differentiation of cytotoxic effectors into memory T lymphocytes. Science 283, 1745–1748 (1999).

    CAS  PubMed  Google Scholar 

  176. Bannard, O., Kraman, M. & Fearon, D. T. Secondary replicative function of CD8+ T cells that had developed an effector phenotype. Science 323, 505–509 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Jacob, J. & Baltimore, D. Modelling T-cell memory by genetic marking of memory T cells in vivo. Nature 399, 593–597 (1999).

    CAS  PubMed  Google Scholar 

  178. Herndler-Brandstetter, D. et al. KLRG1+ effector CD8+ T cells lose KLRG1, differentiate into all memory T cell lineages, and convey enhanced protective immunity. Immunity 48, 716–729.e8 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Youngblood, B. et al. Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature 552, 404–409 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Chang, J. T. et al. Asymmetric proteasome segregation as a mechanism for unequal partitioning of the transcription factor T-bet during T lymphocyte division. Immunity 34, 492–504 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Chang, J. T. et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315, 1687–1691 (2007).

    CAS  PubMed  Google Scholar 

  182. D’Souza, W. N. & Hedrick, S. M. Cutting edge: latecomer CD8 T cells are imprinted with a unique differentiation program. J. Immunol. 177, 777–781 (2006).

    PubMed  Google Scholar 

  183. Badovinac, V. P., Messingham, K. A., Jabbari, A., Haring, J. S. & Harty, J. T. Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nat. Med. 11, 748–756 (2005).

    CAS  PubMed  Google Scholar 

  184. Badovinac, V. P., Porter, B. B. & Harty, J. T. CD8+ T cell contraction is controlled by early inflammation. Nat. Immunol. 5, 809–817 (2004).

    CAS  PubMed  Google Scholar 

  185. Sarkar, S. et al. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J. Exp. Med. 205, 625–640 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Zehn, D., Roepke, S., Weakly, K., Bevan, M. J. & Prlic, M. Inflammation and TCR signal strength determine the breadth of the T cell response in a bim-dependent manner. J. Immunol. 192, 200–205 (2014).

    CAS  PubMed  Google Scholar 

  187. Graef, P. et al. Serial transfer of single-cell-derived immunocompetence reveals stemness of CD8+ central memory T cells. Immunity 41, 116–126 (2014).

    CAS  PubMed  Google Scholar 

  188. Borsa, M. et al. Modulation of asymmetric cell division as a mechanism to boost CD8+ T cell memory. Sci. Immunol. 4, eaav1730 (2019).

    CAS  PubMed  Google Scholar 

  189. Ciocca, M. L., Barnett, B. E., Burkhardt, J. K., Chang, J. T. & Reiner, S. L. Cutting edge: asymmetric memory T cell division in response to rechallenge. J. Immunol. 188, 4145–4148 (2012).

    CAS  PubMed  Google Scholar 

  190. Kinjyo, I. et al. Real-time tracking of cell cycle progression during CD8+ effector and memory T-cell differentiation. Nat. Commun. 6, 6301 (2015).

    CAS  PubMed  Google Scholar 

  191. Bezman, N. A. et al. Molecular definition of the identity and activation of natural killer cells. Nat. Immunol. 13, 1000–1009 (2012). This important early resource from the Immgen Consortium analyses the transcriptome of NK cells during development and activation, and compares it with that of CD8+ T cells in similar states.

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Kuijpers, T. W. et al. Human NK cells can control CMV infection in the absence of T cells. Blood 112, 914–915 (2008).

    CAS  PubMed  Google Scholar 

  193. Foley, B. et al. Human cytomegalovirus (CMV)-induced memory-like NKG2C+ NK cells are transplantable and expand in vivo in response to recipient CMV antigen. J. Immunol. 189, 5082–5088 (2012).

    CAS  PubMed  Google Scholar 

  194. Romee, R. et al. Cytokine activation induces human memory-like NK cells. Blood 120, 4751–4760 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Jamieson, A. M., Isnard, P., Dorfman, J. R., Coles, M. C. & Raulet, D. H. Turnover and proliferation of NK cells in steady state and lymphopenic conditions. J. Immunol. 172, 864–870 (2004).

    CAS  PubMed  Google Scholar 

  196. Prlic, M., Blazar, B. R., Farrar, M. A. & Jameson, S. C. In vivo survival and homeostatic proliferation of natural killer cells. J. Exp. Med. 197, 967–976 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Nabekura, T. & Lanier, L. L. Tracking the fate of antigen-specific versus cytokine-activated natural killer cells after cytomegalovirus infection. J. Exp. Med. 213, 2745–2758 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Romee, R. et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Transl Med. 8, 357ra123 (2016).

    PubMed  PubMed Central  Google Scholar 

  199. Liu, E. et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N. Engl. J. Med. 382, 545–553 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Hsu, J. et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Invest. 128, 4654–4668 (2018).

    PubMed  PubMed Central  Google Scholar 

  201. Andre, P. et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731–1743 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors apologize to those whose important contributions could not be discussed owing to space limitations. They thank K. Schober, V. Buchholz and L. Lanier for helpful discussions and reading of the manuscript. J.C.S. is supported by the Ludwig Center for Cancer Immunotherapy, the American Cancer Society, the Burroughs Wellcome Fund and the US National Institutes of Health (AI100874, AI130043 and P30CA008748).

Author information

Author notes

  1. These authors contributed equally to this work: Nicholas M. Adams, Simon Grassmann

Authors and Affiliations

  1. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Nicholas M. Adams, Simon Grassmann & Joseph C. Sun

  2. Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, USA

    Joseph C. Sun

Authors
  1. Nicholas M. Adams
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simon Grassmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joseph C. Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Joseph C. Sun.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Immunology thanks R. Van Lier and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Clonal expansion

The process by which individual antigen-specific innate and adaptive lymphocytes robustly proliferate following recognition of their cognate ligand, giving rise to a large pool of progeny that bear the same antigen specificity (clones). Clonal expansion coincides with selection and differentiation of the responding lymphocytes to generate a multitude of cell fates.

Immunological memory

The ability of the immune system to quickly and specifically recognize an antigen that the body has previously encountered and initiate a more robust recall response. Although heightened responsiveness is a central feature of memory, true immunological memory is unique and requires that this results from antigen-specific clonal expansion and yields long-lived progeny. Although previously attributed solely to adaptive immune cells, we now appreciate that natural killer cells exhibit immunological memory, most clearly in the setting of cytomegalovirus infection.

Epigenetic regulation

A combination of chromatin modifications (such as DNA methylation, histone post-translational modifications, chromatin accessibility and higher-order chromatin architecture) that regulate gene expression. The function of a given transcription factor depends not only on its expression but also on a favourable epigenetic state at regulatory elements that supports its binding and activity. Furthermore, transcription factors can reinforce their transcriptional programme by modifying the epigenetic landscape at their target genes.

NK cell education

The process by which natural killer (NK) cells acquire functional competence. Education is contingent upon stochastically expressed inhibitory NK cell receptors engaging their ligand, self-MHC class I, thus ensuring that NK cells are sensitive to self-MHC class I. NK cell education is intricately linked to one prominent mechanism of NK cell-mediated cytotoxicity (that is, ‘missing self’ recognition), in which cells lacking self-MHC class I are susceptible to NK cell killing.

Avidity

The overall binding to a specific target through multiple receptor–ligand interactions. This is in contrast to affinity, which describes the binding strength of a monomeric receptor–ligand interaction (as in a single T cell receptor–peptide–MHC). Increased avidity can be achieved through a higher density of cell surface receptors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Adams, N.M., Grassmann, S. & Sun, J.C. Clonal expansion of innate and adaptive lymphocytes. Nat Rev Immunol 20, 694–707 (2020). https://doi.org/10.1038/s41577-020-0307-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-020-0307-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing