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Antigen-inexperienced memory CD8+ T cells: where they come from and why we need them


Memory-phenotype CD8+ T cells exist in substantial numbers within hosts that have not been exposed to either foreign antigen or overt lymphopenia. These antigen-inexperienced memory-phenotype T cells can be divided into two major subsets: 'innate memory' T cells and 'virtual memory' T cells. Although these two subsets are nearly indistinguishable by surface markers alone, notable developmental and functional differences exist between the two subsets, which suggests that they represent distinct populations. In this Opinion article, we review the available literature on each subset, highlighting the key differences between these populations. Furthermore, we suggest a unifying model for the categorization of antigen-inexperienced memory-phenotype CD8+ T cells.

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Figure 1: A model of the development of innate memory and virtual memory T cells.
Figure 2: The influence of cytokine complexes on naive and memory CD8+ T cell subsets.


  1. 1

    Dobber, R., Hertogh-Huijbregts, A., Rozing, J., Bottomly, K. & Nagelkerken, L. The involvement of the intestinal microflora in the expansion of CD4+ T cells with a naive phenotype in the periphery. Dev. Immunol. 2, 141–150 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Le Campion, A. et al. Naive T cells proliferate strongly in neonatal mice in response to self-peptide/self-MHC complexes. Proc. Natl Acad. Sci. USA 99, 4538–4543 (2002).

    CAS  PubMed  Google Scholar 

  3. 3

    Haluszczak, C. et al. The antigen-specific CD8+ T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion. J. Exp. Med. 206, 435–448 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Goldrath, A. W. & Bevan, M. J. Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 11, 183–190 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Goldrath, A. W., Bogatzki, L. Y. & Bevan, M. J. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J. Exp. Med. 192, 557–564 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Kieper, W. C. & Jameson, S. C. Homeostatic expansion and phenotypic conversion of naive T cells in response to self peptide/MHC ligands. Proc. Natl Acad. Sci. USA 96, 13306–13311 (1999).

    CAS  PubMed  Google Scholar 

  7. 7

    Surh, C. D. & Sprent, J. Homeostatic T cell proliferation: how far can T cells be activated to self-ligands? J. Exp. Med. 192, 9–14 (2000).

    PubMed Central  Google Scholar 

  8. 8

    Cho, J. H. et al. An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2. J. Exp. Med. 204, 1787–1801 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Stoklasek, T. A., Colpitts, S. L., Smilowitz, H. M. & Lefrançois, L. MHC class I and TCR avidity control the CD8 T cell response to IL-15/IL-15Rα complex. J. Immunol. 185, 6857–6865 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Sandau, M. M., Winstead, C. J. & Jameson, S. C. IL-15 is required for sustained lymphopenia-driven proliferation and accumulation of CD8 T cells. J. Immunol. 179, 120–125 (2007).

    CAS  PubMed  Google Scholar 

  11. 11

    Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrançois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat. Immunol. 1, 426–432 (2000).

    CAS  PubMed  Google Scholar 

  12. 12

    Tan, J. T. et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl Acad. Sci. USA 98, 8732–8737 (2001).

    CAS  PubMed  Google Scholar 

  13. 13

    Guimond, M. et al. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat. Immunol. 10, 149–157 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Napolitano, L. A. et al. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat. Med. 7, 73–79 (2001).

    CAS  PubMed  Google Scholar 

  15. 15

    Fry, T. J. et al. A potential role for interleukin-7 in T-cell homeostasis. Blood 97, 2983–2990 (2001).

    CAS  PubMed  Google Scholar 

  16. 16

    Ernst, B., Lee, D.-S., Chang, J. M., Sprent, J. & Surh, C. D. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173–181 (1999).

    CAS  PubMed  Google Scholar 

  17. 17

    Cho, J. H., Kim, H. O., Surh, C. D. & Sprent, J. T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis. Immunity 32, 214–226 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Varshney, P., Yadav, V. & Saini, N. Lipid rafts in immune signalling: current progress and future perspective. Immunology 149, 13–24 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Takada, K. & Jameson, S. C. Self-class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels. J. Exp. Med. 206, 2253–2269 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Goldrath, A. W., Luckey, C. J., Park, R., Benoist, C. & Mathis, D. The molecular program induced in T cells undergoing homeostatic proliferation. Proc. Natl Acad. Sci. USA 101, 16885–16890 (2004).

    CAS  PubMed  Google Scholar 

  21. 21

    Wyss, L. et al. Affinity for self antigen selects Treg cells with distinct functional properties. Nat. Immunol. 17, 1093–1101 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Atherly, L. O. et al. The Tec family tyrosine kinases Itk and Rlk regulate the development of conventional CD8+ T Cells. Immunity 25, 79–91 (2006).

    CAS  PubMed  Google Scholar 

  23. 23

    Berg, L. J. Signalling through TEC kinases regulates conventional versus innate CD8+ T-cell development. Nat. Rev. Immunol. 7, 479–485 (2007).

    CAS  PubMed  Google Scholar 

  24. 24

    Broussard, C. et al. Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk. Immunity 25, 93–104 (2006).

    CAS  PubMed  Google Scholar 

  25. 25

    Horai, R. et al. Requirements for selection of conventional and innate T lymphocyte lineages. Immunity 27, 775–785 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Weinreich, M. A., Odumade, O. A., Jameson, S. C. & Hogquist, K. A. T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells. Nat. Immunol. 11, 709–716 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Sosinowski, T. et al. CD8α+ dendritic cell trans presentation of IL-15 to naive CD8+ T cells produces antigen-inexperienced T cells in the periphery with memory phenotype and function. J. Immunol. 190, 1936–1947 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    White, J. T. et al. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat. Commun. 7, 11291 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Lee, Y. J., Jameson, S. C. & Hogquist, K. A. Alternative memory in the CD8 T cell lineage. Trends Immunol. 32, 50–56 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Jameson, S. C., Lee, Y. J. & Hogquist, K. A. in Advances in Immunology Vol. 126 Ch. 4 (ed. Frederick, W. A.) 3–213 (Academic Press, 2015).

    Google Scholar 

  31. 31

    Van Kaer, L. Innate and virtual memory T cells in man. Eur. J. Immunol. 45, 1916–1920 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    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 

  33. 33

    Spits, H. & Cupedo, T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 30, 647–675 (2012).

    CAS  PubMed  Google Scholar 

  34. 34

    Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445–456 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Qiu, Y., Peng, K., Liu, M., Xiao, W. & Yang, H. CD8αα TCRαβ intraepithelial lymphocytes in the mouse gut. Dig. Dis. Sci. 61, 1451–1460 (2016).

    CAS  PubMed  Google Scholar 

  36. 36

    Fukuyama, T. et al. Histone acetyltransferase CBP is vital to demarcate conventional and innate CD8+ T-cell development. Mol. Cell. Biol. 29, 3894–3904 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Verykokakis, M., Boos, M. D., Bendelac, A. & Kee, B. L. SAP protein-dependent natural killer T-like cells regulate the development of CD8+ T cells with innate lymphocyte characteristics. Immunity 33, 203–215 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Lee, Y. J., Holzapfel, K. L., Zhu, J., Jameson, S. C. & Hogquist, K. A. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat. Immunol. 14, 1146–1154 (2013).

    CAS  PubMed  Google Scholar 

  39. 39

    Weinreich, M. A. et al. KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors. Immunity 31, 122–130 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Lee, Y. J. et al. Tissue-specific distribution of iNKT cells impacts their cytokine response. Immunity 43, 566–578 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Koschella, M., Voehringer, D. & Pircher, H. CD40 ligation in vivo induces bystander proliferation of memory phenotype CD8 T cells. J. Immunol. 172, 4804–4811 (2004).

    CAS  PubMed  Google Scholar 

  42. 42

    Moon, J. J. et al. Naive CD4+ T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27, 203–213 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Akue, A. D., Lee, J. Y. & Jameson, S. C. Derivation and maintenance of virtual memory CD8 T cells. J. Immunol. 188, 2516–2523 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Lee, J. Y., Hamilton, S. E., Akue, A. D., Hogquist, K. A. & Jameson, S. C. Virtual memory CD8 T cells display unique functional properties. Proc. Natl Acad. Sci. USA 110, 13498–13503 (2013).

    CAS  PubMed  Google Scholar 

  45. 45

    Tripathi, P. et al. IL-4 and IL-15 promotion of virtual memory CD8+ T cells is determined by genetic background. Eur. J. Immunol. 46, 2333–2339 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Renkema, K. R. et al. IL-4 sensitivity shapes the peripheral CD8+ T cell pool and response to infection. J. Exp. Med. 213, 1319–1329 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Fulton, R. B. et al. The TCR's sensitivity to self peptide-MHC dictates the ability of naive CD8+ T cells to respond to foreign antigens. Nat. Immunol. 16, 107–117 (2015).

    CAS  PubMed  Google Scholar 

  48. 48

    Kurzweil, V., LaRoche, A. & Oliver, P. M. Increased peripheral IL-4 leads to an expanded virtual memory CD8+ population. J. Immunol. 192, 5643–5651 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Martinet, V. et al. Type I interferons regulate eomesodermin expression and the development of unconventional memory CD8+ T cells. Nat. Commun. 6, 7089 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Ventre, E. et al. Negative regulation of NKG2D expression by IL-4 in memory CD8 T cells. J. Immunol. 189, 3480–3489 (2012).

    CAS  PubMed  Google Scholar 

  51. 51

    Morris, S. C. et al. Endogenously produced IL-4 nonredundantly stimulates CD8+ T cell proliferation. J. Immunol. 182, 1429–1438 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Boyman, O., Kovar, M., Rubinstein, M. P., Surh, C. D. & Sprent, J. Selective stimulation of T cell subsets with antibody–cytokine immune complexes. Science 311, 1924–1927 (2006).

    CAS  PubMed  Google Scholar 

  53. 53

    Carlson, C. M. et al. Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature 442, 299–302 (2006).

    CAS  PubMed  Google Scholar 

  54. 54

    Takada, K. et al. Kruppel-like factor 2 is required for trafficking but not quiescence in postactivated T cells. J. Immunol. 186, 775–783 (2011).

    CAS  PubMed  Google Scholar 

  55. 55

    Ku, C. C., Murakami, M., Sakamoto, A., Kappler, J. & Marrack, P. Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288, 675–678 (2000).

    CAS  PubMed  Google Scholar 

  56. 56

    Chu, T. et al. Bystander-activated memory CD8 T cells control early pathogen load in an innate-like, NKG2D-dependent manner. Cell Rep. 3, 701–708 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Rudd, B. D. et al. Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions. Proc. Natl Acad. Sci. USA 108, 13694–13699 (2011).

    CAS  PubMed  Google Scholar 

  58. 58

    Correia, M. P. et al. Hepatocytes and IL-15: a favorable microenvironment for T cell survival and CD8+ T cell differentiation. J. Immunol. 182, 6149–6159 (2009).

    CAS  PubMed  Google Scholar 

  59. 59

    Doherty, D. G. Immunity, tolerance and autoimmunity in the liver: a comprehensive review. J. Autoimmun. 66, 60–75 (2016).

    CAS  PubMed  Google Scholar 

  60. 60

    Jenne, C. N. & Kubes, P. Immune surveillance by the liver. Nat. Immunol. 14, 996–1006 (2013).

    CAS  PubMed  Google Scholar 

  61. 61

    Crispe, I. N. Liver antigen-presenting cells. J. Hepatol. 54, 357–365 (2011).

    CAS  PubMed  Google Scholar 

  62. 62

    Knolle, P. et al. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J. Hepatol. 22, 226–229 (1995).

    CAS  PubMed  Google Scholar 

  63. 63

    Zhang, M., Xu, S., Han, Y. & Cao, X. Apoptotic cells attenuate fulminant hepatitis by priming Kupffer cells to produce interleukin-10 through membrane-bound TGF-β. Hepatology 53, 306–316 (2011).

    CAS  PubMed  Google Scholar 

  64. 64

    Lee, W. Y. et al. An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nat. Immunol. 11, 295–302 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Spellberg, B. & Edwards, J. E. Type 1/type 2 immunity in infectious diseases. Clin. Infect. Dis. 32, 76–102 (2001).

    CAS  PubMed  Google Scholar 

  66. 66

    Byrne, J. A., Stankovic, A. K. & Cooper, M. D. A novel subpopulation of primed T cells in the human fetus. J. Immunol. 152, 3098–3106 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Min, H. S. et al. MHC class II-restricted interaction between thymocytes plays an essential role in the production of innate CD8+ T cells. J. Immunol. 186, 5749–5757 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Lee, Y. J. et al. Generation of PLZF+ CD4+ T cells via MHC class II–dependent thymocyte–thymocyte interaction is a physiological process in humans. J. Exp. Med. 207, 237–246 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Jacomet, F. et al. Evidence for eomesodermin-expressing innate-like CD8+ KIR/NKG2A+ T cells in human adults and cord blood samples. Eur. J. Immunol. 45, 1926–1933 (2015).

    CAS  PubMed  Google Scholar 

  70. 70

    Azzam, H. S. et al. Fine tuning of TCR signaling by CD5. J. Immunol. 166, 5464–5472 (2001).

    CAS  PubMed  Google Scholar 

  71. 71

    Azzam, H. S. et al. CD5 expression is developmentally regulated by T cell receptor (TCR) signals and TCR avidity. J. Exp. Med. 188, 2301–2311 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Herndler-Brandstetter, D. et al. Post-thymic regulation of CD5 levels in human memory T cells is inversely associated with the strength of responsiveness to interleukin-15. Hum. Immunol. 72, 627–631 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Geginat, J., Lanzavecchia, A. & Sallusto, F. Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood 101, 4260–4266 (2003).

    CAS  PubMed  Google Scholar 

  74. 74

    Larbi, A. & Fulop, T. From “truly naive” to “exhausted senescent” T cells: when markers predict functionality. Cytometry A 85, 25–35 (2014).

    PubMed  Google Scholar 

  75. 75

    Moran, A. E. et al. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279–1289 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    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 

  77. 77

    Romero, P. et al. Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J. Immunol. 178, 4112–4119 (2007).

    CAS  PubMed  Google Scholar 

  78. 78

    Su, L. F., Kidd, B. A., Han, A., Kotzin, J. J. & Davis, M. M. Virus-specific CD4+ memory-phenotype T cells are abundant in unexposed adults. Immunity 38, 373–383 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Marusina, A. I. et al. CD4+ virtual memory: antigen-inexperienced T cells reside in the naive, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity. J. Autoimmun. 77, 76–88 (2017).

    CAS  PubMed  Google Scholar 

  80. 80

    Schüler, T., Hämmerling, G. J. & Arnold, B. Cutting edge: IL-7-dependent homeostatic proliferation of CD8+ T cells in neonatal mice allows the generation of long-lived natural memory T cells. J. Immunol. 172, 15–19 (2004).

    PubMed  Google Scholar 

  81. 81

    Lynch, H. E. et al. Thymic involution and immune reconstitution. Trends Immunol. 30, 366–373 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Schwab, R. et al. Expanded CD4+ and CD8+ T cell clones in elderly humans. J. Immunol. 158, 4493–4499 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Mehlhop-Williams, E. R. & Bevan, M. J. Memory CD8+ T cells exhibit increased antigen threshold requirements for recall proliferation. J. Exp. Med. 211, 345–356 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Else, K. J., Finkelman, F. D., Maliszewski, C. R. & Grencis, R. K. Cytokine-mediated regulation of chronic intestinal helminth infection. J. Exp. Med. 179, 347–351 (1994).

    CAS  PubMed  Google Scholar 

  85. 85

    Hamann, D. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186, 1407–1418 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

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The authors wish to thank C. Suhr, S. Jameson and D. Hildeman for their helpful communications. This work was funded by US National Institutes of Health grants AI101205 and AI066121.

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Correspondence to Ross M. Kedl.

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White, J., Cross, E. & Kedl, R. Antigen-inexperienced memory CD8+ T cells: where they come from and why we need them. Nat Rev Immunol 17, 391–400 (2017).

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