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The full spectrum of human naive T cells

Nature Reviews Immunology volume 18, pages 363–373 (2018)Cite this article

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Abstract

Naive T cells have long been regarded as a developmentally synchronized and fairly homogeneous and quiescent cell population, the size of which depends on age, thymic output and prior infections. However, there is increasing evidence that naive T cells are heterogeneous in phenotype, function, dynamics and differentiation status. Current strategies to identify naive T cells should be adjusted to take this heterogeneity into account. Here, we provide an integrated, revised view of the naive T cell compartment and discuss its implications for healthy ageing, neonatal immunity and T cell reconstitution following haematopoietic stem cell transplantation.

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Fig. 1: Schematic representation of naive T cell differentiation.
Fig. 2: Cell dynamics of the different CD45RA+CD4+ T cell subsets during ageing.
Fig. 3: Neonatal versus adult naive T cell characteristics.
Fig. 4: Naive T cell characteristics following haematopoietic stem cell transplantation.

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References

  1. den Braber, I. et al. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 36, 288–297 (2012). This study demonstrates that naive T cell maintenance occurs fundamentally differently in mice and humans.

    Article  CAS  Google Scholar 

  2. Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

    Article  PubMed  CAS  Google Scholar 

  3. Gibbons, D. et al. Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants. Nat. Med. 20, 1206–1210 (2014). This study demonstrates that T cells from newborn babies can respond to activation by expressing high levels of IL-8.

    Article  PubMed  CAS  Google Scholar 

  4. Takada, K. & Jameson, S. C. Naive T cell homeostasis: from awareness of space to a sense of place. Nat. Rev. Immunol. 9, 823–832 (2009).

    Article  PubMed  CAS  Google Scholar 

  5. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Fink, P. J. The biology of recent thymic emigrants. Annu. Rev. Immunol. 31, 31–50 (2013).

    Article  PubMed  CAS  Google Scholar 

  8. Haines, C. J. et al. Human CD4+ T cell recent thymic emigrants are identified by protein tyrosine kinase 7 and have reduced immune function. J. Exp. Med. 206, 275–285 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Kohler, S. et al. Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults. Eur. J. Immunol. 35, 1987–1994 (2005).

    Article  PubMed  CAS  Google Scholar 

  10. Kwan, A. et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA 312, 729–738 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Muraro, P. A. et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J. Exp. Med. 201, 805–816 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. van der Spek, J., Groenwold, R. H., van der Burg, M. & van Montfrans, J. M. TREC based newborn screening for severe combined immunodeficiency disease: a systematic review. J. Clin. Immunol. 35, 416–430 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Ye, P. & Kirschner, D. E. Measuring emigration of human thymocytes by T-cell receptor excision circles. Crit. Rev. Immunol. 22, 483–497 (2002).

    Article  PubMed  CAS  Google Scholar 

  14. Douek, D. C. et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690–695 (1998).

    Article  PubMed  CAS  Google Scholar 

  15. Hazenberg, M. D. et al. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat. Med. 6, 1036–1042 (2000).

    Article  PubMed  CAS  Google Scholar 

  16. Hazenberg, M. D., Verschuren, M. C., Hamann, D., Miedema, F. & van Dongen, J. J. T cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach, and guidelines for interpretation. J. Mol. Med. 79, 631–640 (2001).

    Article  PubMed  CAS  Google Scholar 

  17. Kilpatrick, R. D. et al. Homeostasis of the naive CD4+ T cell compartment during aging. J. Immunol. 180, 1499–1507 (2008).

    Article  PubMed  CAS  Google Scholar 

  18. Kimmig, S. et al. Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J. Exp. Med. 195, 789–794 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Kohler, S. & Thiel, A. Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets. Blood 113, 769–774 (2009).

    Article  PubMed  CAS  Google Scholar 

  20. Bains, I., Yates, A. J. & Callard, R. E. Heterogeneity in thymic emigrants: implications for thymectomy and immunosenescence. PLoS ONE 8, e49554 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. van den Broek, T. et al. Neonatal thymectomy reveals differentiation and plasticity within human naive T cells. J. Clin. Invest. 126, 1126–1136 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Fornasa, G. et al. TCR stimulation drives cleavage and shedding of the ITIM receptor CD31. J. Immunol. 184, 5485–5492 (2010).

    Article  PubMed  CAS  Google Scholar 

  23. Vrisekoop, N. T-cell dynamics in healthy and HIV-infected individuals Ch. 7 Thesis, Utrecht Univ. (2007).

  24. McFarland, R. D., Douek, D. C., Koup, R. A. & Picker, L. J. Identification of a human recent thymic emigrant phenotype. Proc. Natl Acad. Sci. USA 97, 4215–4220 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Das, A. et al. Adaptive from innate: human IFN-gamma+CD4+ T cells can arise directly from CXCL8-producing recent thymic emigrants in babies and adults. J. Immunol. 199, 1696–1705 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Pekalski, M. L. et al. Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2. JCI Insight 2, e93739 (2017).

    Article  PubMed Central  Google Scholar 

  27. Friesen, T. J., Ji, Q. & Fink, P. J. Recent thymic emigrants are tolerized in the absence of inflammation. J. Exp. Med. 213, 913–920 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. van der Geest, K. S. et al. Low-affinity TCR engagement drives IL-2-dependent post-thymic maintenance of naive CD4+ T cells in aged humans. Aging Cell 14, 744–753 (2015). This study demonstrates further naive T cell heterogeneity by the expression of CD25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Pekalski, M. L. et al. Postthymic expansion in human CD4 naive T cells defined by expression of functional high-affinity IL-2 receptors. J. Immunol. 190, 2554–2566 (2013).

    Article  PubMed  CAS  Google Scholar 

  30. Berkley, A. M., Hendricks, D. W., Simmons, K. B. & Fink, P. J. Recent thymic emigrants and mature naive T cells exhibit differential DNA methylation at key cytokine loci. J. Immunol. 190, 6180–6186 (2013).

    Article  PubMed  CAS  Google Scholar 

  31. Cunningham, C. A., Bergsbaken, T. & Fink, P. J. Cutting edge: defective aerobic glycolysis defines the distinct effector function in antigen-activated CD8+ recent thymic emigrants. J. Immunol. 198, 4575–4580 (2017).

    Article  PubMed  CAS  Google Scholar 

  32. LaMere, S. A. et al. H3K27 methylation dynamics during CD4 T cell activation: regulation of JAK/STAT and IL12RB2 expression by JMJD3. J. Immunol. 199, 3158–3175 (2017).

    Article  PubMed  CAS  Google Scholar 

  33. Durek, P. et al. Epigenomic profiling of human CD4+ T cells supports a linear differentiation model and highlights molecular regulators of memory development. Immunity 45, 1148–1161 (2016).

    Article  PubMed  CAS  Google Scholar 

  34. Moskowitz, D. M. et al. Epigenomics of human CD8 T cell differentiation and aging. Sci. Immunol. 2, eaag0192 (2017).

    Google Scholar 

  35. Altorok, N. et al. Genome-wide DNA methylation patterns in naive CD4+ T cells from patients with primary Sjogren’s syndrome. Arthritis Rheumatol. 66, 731–739 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Coit, P. et al. Epigenetic reprogramming in naive CD4+ T cells favoring T cell activation and non-Th1 effector T cell immune response as an early event in lupus flares. Arthritis Rheumatol. 68, 2200–2209 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Heninger, A. K. et al. A divergent population of autoantigen-responsive CD4+ T cells in infants prior to beta cell autoimmunity. Sci. Transl Med. 9, eaaf8848 (2017).

    Article  PubMed  CAS  Google Scholar 

  38. Houston, E. G. Jr, Higdon, L. E. & Fink, P. J. Recent thymic emigrants are preferentially incorporated only into the depleted T-cell pool. Proc. Natl Acad. Sci. USA 108, 5366–5371 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Berzins, S. P., Boyd, R. L. & Miller, J. F. The role of the thymus and recent thymic migrants in the maintenance of the adult peripheral lymphocyte pool. J. Exp. Med. 187, 1839–1848 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Berzins, S. P., Godfrey, D. I., Miller, J. F. & Boyd, R. L. A central role for thymic emigrants in peripheral T cell homeostasis. Proc. Natl Acad. Sci. USA 96, 9787–9791 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. van Hoeven, V. et al. Dynamics of recent thymic emigrants in young adult mice. Front. Immunol. 8, 933 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Dong, J. et al. Homeostatic properties and phenotypic maturation of murine CD4+ pre-thymic emigrants in the thymus. PLoS ONE 8, e56378 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Houston, E. G. Jr & Fink, P. J. MHC drives TCR repertoire shaping, but not maturation, in recent thymic emigrants. J. Immunol. 183, 7244–7249 (2009).

    Article  PubMed  CAS  Google Scholar 

  44. Hogan, T., Gossel, G., Yates, A. J. & Seddon, B. Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice. Proc. Natl Acad. Sci. USA 112, E6917–E6926 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Di Rosa, F. & Pabst, R. The bone marrow: a nest for migratory memory T cells. Trends Immunol. 26, 360–366 (2005).

    Article  PubMed  CAS  Google Scholar 

  46. Thome, J. J. et al. Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues. Nat. Med. 22, 72–77 (2016).This study reveals early-life T cell distribution and function in different tissue compartments.

    Article  PubMed  CAS  Google Scholar 

  47. Lewis, M., Tarlton, J. F. & Cose, S. Memory versus naive T-cell migration. Immunol. Cell Biol. 86, 226–231 (2008).

    Article  PubMed  CAS  Google Scholar 

  48. Thome, J. J. et al. Longterm maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites. Sci. Immunol. 1, eaah6506 (2016). This study reveals long-term maintenance of human naive T cells in lymphoid tissues with site-specific clonal expansions of naive T cells.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Wong, M. T. et al. A high-dimensional atlas of human T cell diversity reveals tissue-specific trafficking and cytokine signatures. Immunity 45, 442–456 (2016).

    Article  PubMed  CAS  Google Scholar 

  50. Centers for Disease Control and Prevention. Estimates of deaths associated with seasonal influenza—United States, 1976–2007. MMWR Morb. Mortal. Wkly Rep. 59, 1057–1062 (2010).

    Google Scholar 

  51. Gardner, P. & Pabbatireddy, S. Vaccines for women age 50 and older. Emerg. Infect. Dis. 10, 1990–1995 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Steinmann, G. G., Klaus, B. & Muller-Hermelink, H. K. The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand. J. Immunol. 22, 563–575 (1985).

    Article  PubMed  CAS  Google Scholar 

  53. Westera, L. et al. Lymphocyte maintenance during healthy aging requires no substantial alterations in cellular turnover. Aging Cell 14, 219–227 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Tsukamoto, H., Huston, G. E., Dibble, J., Duso, D. K. & Swain, S. L. Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. J. Immunol. 185, 4535–4544 (2010).

    Article  PubMed  CAS  Google Scholar 

  55. Sauce, D. et al. Lymphopenia-driven homeostatic regulation of naive T cells in elderly and thymectomized young adults. J. Immunol. 189, 5541–5548 (2012).

    Article  PubMed  CAS  Google Scholar 

  56. Cicin-Sain, L. et al. Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates. Proc. Natl Acad. Sci. USA 104, 19960–19965 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Gardner, I. D. The effect of aging on susceptibility to infection. Rev. Infect. Dis. 2, 801–810 (1980).

    Article  PubMed  CAS  Google Scholar 

  58. Miller, R. A. The aging immune system: primer and prospectus. Science 273, 70–74 (1996).

    Article  PubMed  CAS  Google Scholar 

  59. Akbar, A. N. & Fletcher, J. M. Memory T cell homeostasis and senescence during aging. Curr. Opin. Immunol. 17, 480–485 (2005).

    Article  PubMed  CAS  Google Scholar 

  60. Haynes, L., Eaton, S. M., Burns, E. M., Randall, T. D. & Swain, S. L. CD4 T cell memory derived from young naive cells functions well into old age, but memory generated from aged naive cells functions poorly. Proc. Natl Acad. Sci. USA 100, 15053–15058 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Britanova, O. V. et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J. Immunol. 192, 2689–2698 (2014).

    Article  PubMed  CAS  Google Scholar 

  62. Britanova, O. V. et al. Dynamics of individual T cell repertoires: from cord blood to centenarians. J. Immunol. 196, 5005–5013 (2016).

    Article  PubMed  CAS  Google Scholar 

  63. Shifrut, E. et al. CD4(+) T cell-receptor repertoire diversity is compromised in the spleen but not in the bone marrow of aged mice due to private and sporadic clonal expansions. Front. Immunol. 4, 379 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Gibson, K. L. et al. B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 8, 18–25 (2009).

    Article  PubMed  CAS  Google Scholar 

  65. Qi, Q. et al. Diversity and clonal selection in the human T-cell repertoire. Proc. Natl Acad. Sci. USA 111, 13139–13144 (2014). This study demonstrates that the TCR repertoire of naive T cells only modestly decreases during healthy ageing.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Ferrando-Martinez, S. et al. Age-related deregulation of naive T cell homeostasis in elderly humans. Age 33, 197–207 (2011).

    Article  PubMed  CAS  Google Scholar 

  67. Li, G. et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat. Med. 18, 1518–1524 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Adkins, B., Leclerc, C. & Marshall-Clarke, S. Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4, 553–564 (2004).

    Article  PubMed  CAS  Google Scholar 

  69. Galindo-Albarran, A. O. et al. CD8+ T cells from human neonates are biased toward an innate immune response. Cell Rep. 17, 2151–2160 (2016). This study demonstrates that neonatal CD8 T cells have a distinct epigenetic landscape that is biased towards an innate immune response.

    Article  PubMed  CAS  Google Scholar 

  70. Crespo, M. et al. Neonatal T-cell maturation and homing receptor responses to Toll-like receptor ligands differ from those of adult naive T cells: relationship to prematurity. Pediatr. Res. 71, 136–143 (2012).

    Article  PubMed  CAS  Google Scholar 

  71. Alexander-Miller, M. A. Vaccines against respiratory viral pathogens for use in neonates: opportunities and challenges. J. Immunol. 193, 5363–5369 (2014).

    Article  PubMed  CAS  Google Scholar 

  72. Dowling, D. J. et al. TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth. JCI Insight 2, e91020 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Heining, C. et al. Lymphocyte reconstitution following allogeneic hematopoietic stem cell transplantation: a retrospective study including 148 patients. Bone Marrow Transplant. 39, 613–622 (2007).

    Article  PubMed  CAS  Google Scholar 

  74. Ringhoffer, S., Rojewski, M., Dohner, H., Bunjes, D. & Ringhoffer, M. T-cell reconstitution after allogeneic stem cell transplantation: assessment by measurement of the sjTREC/betaTREC ratio and thymic naive T cells. Haematologica 98, 1600–1608 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Alho, A. C. et al. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood 127, 646–657 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Cieri, N. et al. Generation of human memory stem T cells after haploidentical T-replete hematopoietic stem cell transplantation. Blood 125, 2865–2874 (2015).

    Article  PubMed  CAS  Google Scholar 

  77. Roberto, A. et al. Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation. Blood 125, 2855–2864 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Thiel, A. et al. Direct assessment of thymic reactivation after autologous stem cell transplantation. Acta Haematol. 119, 22–27 (2008).

    Article  PubMed  Google Scholar 

  79. Azevedo, R. I. et al. Long-term immune reconstitution of naive and memory T cell pools after haploidentical hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 19, 703–712 (2013).

    Article  PubMed  CAS  Google Scholar 

  80. Douek, D. C. et al. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355, 1875–1881 (2000).

    Article  PubMed  CAS  Google Scholar 

  81. Hazenberg, M. D. et al. T-Cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events. Blood 99, 3449–3453 (2002).

    Article  PubMed  CAS  Google Scholar 

  82. Kanakry, C. G. et al. Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide. JCI Insight 1, e86252 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Bleakley, M. et al. Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells. Blood 115, 4923–4933 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Distler, E. et al. Alloreactive and leukemia-reactive T cells are preferentially derived from naive precursors in healthy donors: implications for immunotherapy with memory T cells. Haematologica 96, 1024–1032 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Anderson, B. E. et al. Memory CD4+ T cells do not induce graft-versus-host disease. J. Clin. Invest. 112, 101–108 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Bleakley, M. et al. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J. Clin. Invest. 125, 2677–2689 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Politikos, I. & Boussiotis, V. A. The role of the thymus in T-cell immune reconstitution after umbilical cord blood transplantation. Blood 124, 3201–3211 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Sakaguchi, S., Miyara, M., Costantino, C. M. & Hafler, D. A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10, 490–500 (2010).

    Article  PubMed  CAS  Google Scholar 

  89. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  PubMed  CAS  Google Scholar 

  90. Hsieh, C. S., Lee, H. M. & Lio, C. W. Selection of regulatory T cells in the thymus. Nat. Rev. Immunol. 12, 157–167 (2012).

    Article  PubMed  CAS  Google Scholar 

  91. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Caramalho, I. et al. Human regulatory T-cell development is dictated by interleukin-2 and -15 expressed in a non-overlapping pattern in the thymus. J. Autoimmun. 56, 98–110 (2015).

    Article  PubMed  CAS  Google Scholar 

  93. Caramalho, I., Nunes-Cabaco, H., Foxall, R. B. & Sousa, A. E. Regulatory T-cell development in the human thymus. Front Immunol. 6, 395 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Fuertes Marraco, S. A. et al. Long-lasting stem cell-like memory CD8+ T cells with a naive-like profile upon yellow fever vaccination. Sci. Transl Med. 7, 282ra48 (2015).

    Article  PubMed  CAS  Google Scholar 

  95. Gattinoni, L., Speiser, D. E., Lichterfeld, M. & Bonini, C. T memory stem cells in health and disease. Nat. Med. 23, 18–27 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  96. Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Ahmed, R. et al. Human stem cell-like memory T cells are maintained in a state of dynamic flux. Cell Rep. 17, 2811–2818 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Miyama, T. et al. Highly functional T-cell receptor repertoires are abundant in stem memory T cells and highly shared among individuals. Sci. Rep. 7, 3663 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Pulko, V. et al. Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nat. Immunol. 17, 966–975 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Nasi, M. et al. Thymic output and functionality of the IL-7/IL-7 receptor system in centenarians: implications for the neolymphogenesis at the limit of human life. Aging Cell 5, 167–175 (2006).

    Article  PubMed  CAS  Google Scholar 

  101. Collier, F. M. et al. The ontogeny of naive and regulatory CD4(+) T-cell subsets during the first postnatal year: a cohort study. Clin. Transl Immunol. 4, e34 (2015).

    Article  CAS  Google Scholar 

  102. Utsuyama, M. et al. Differential age-change in the numbers of CD4+CD45RA+ and CD4+CD29+ T cell subsets in human peripheral blood. Mech. Ageing Dev 63, 57–68 (1992).

    Article  PubMed  CAS  Google Scholar 

  103. Stulnig, T., Maczek, C., Bock, G., Majdic, O. & Wick, G. Reference intervals for human peripheral blood lymphocyte subpopulations from ‘healthy’ young and aged subjects. Int. Arch. Allergy Immunol. 108, 205–210 (1995).

    Article  PubMed  CAS  Google Scholar 

  104. Wertheimer, A. M. et al. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J. Immunol. 192, 2143–2155 (2014).

    Article  PubMed  CAS  Google Scholar 

  105. Zhang, L. et al. Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy. J. Exp. Med. 190, 725–732 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Rickabaugh, T. M. et al. The dual impact of HIV-1 infection and aging on naive CD4 T-cells: additive and distinct patterns of impairment. PLOS One 6, e16459 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Junge, S. et al. Correlation between recent thymic emigrants and CD31+(PECAM-1) CD4+ T cells in normal individuals during aging and in lymphopenic children. Eur. J. Immunol. 37, 3270–3280 (2007).

    Article  PubMed  CAS  Google Scholar 

  108. Koch, S. et al. Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun. Ageing 5, 6 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Reen, D. J. Activation and functional capacity of human neonatal CD4 T-cells. Vaccine 16, 1401–1408 (1998).

    Article  PubMed  CAS  Google Scholar 

  110. Ikewaki, N., Yamao, H., Kulski, J. K. & Inoko, H. Flow cytometric identification of CD93 expression on naive T lymphocytes (CD4(+)CD45RA (+) cells) in human neonatal umbilical cord blood. J. Clin. Immunol. 30, 723–733 (2010).

    Article  PubMed  CAS  Google Scholar 

  111. Mackall, C. L. & Gress, R. E. Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy. Immunol. Rev. 157, 61–72 (1997).

    Article  PubMed  CAS  Google Scholar 

  112. Mackall, C. L. T-Cell immunodeficiency following cytotoxic antineoplastic therapy: a review. Stem Cells 18, 10–18 (2000).

    Article  PubMed  CAS  Google Scholar 

  113. Akbar, A. N., Timms, A. & Janossy, G. Cellular events during memory T-cell activation in vitro: the UCHL1 (180,000 MW) determinant is newly synthesized after mitosis. Immunology 66, 213–218 (1989).

    PubMed  PubMed Central  CAS  Google Scholar 

  114. Michie, C. A., McLean, A., Alcock, C. & Beverley, P. C. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 360, 264–265 (1992).

    Article  PubMed  CAS  Google Scholar 

  115. Picker, L. J. et al. Control of lymphocyte recirculation in man. I. Differential regulation of the peripheral lymph node homing receptor L-selectin on T cells during the virgin to memory cell transition. J. Immunol. 150, 1105–1121 (1993).

    PubMed  CAS  Google Scholar 

  116. Trowbridge, I. S. & Thomas, M. L. CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development. Annu. Rev. Immunol. 12, 85–116 (1994).

    Article  PubMed  CAS  Google Scholar 

  117. Forster, R., Davalos-Misslitz, A. C. & Rot, A. CCR7 and its ligands: balancing immunity and tolerance. Nat. Rev. Immunol. 8, 362–371 (2008).

    Article  PubMed  CAS  Google Scholar 

  118. Hengel, R. L. et al. Cutting edge: L-selectin (CD62L) expression distinguishes small resting memory CD4+ T cells that preferentially respond to recall antigen. J. Immunol. 170, 28–32 (2003).

    Article  PubMed  CAS  Google Scholar 

  119. Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).

    Article  PubMed  CAS  Google Scholar 

  120. Warnock, R. A., Askari, S., Butcher, E. C. & von Andrian, U. H. Molecular mechanisms of lymphocyte homing to peripheral lymph nodes. J. Exp. Med. 187, 205–216 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Marelli-Berg, F. M., Clement, M., Mauro, C. & Caligiuri, G. An immunologist’s guide to CD31 function in T-cells. J. Cell Sci. 126, 2343–2352 (2013).

    Article  PubMed  CAS  Google Scholar 

  122. Camerini, D., Walz, G., Loenen, W. A., Borst, J. & Seed, B. The T cell activation antigen CD27 is a member of the nerve growth factor/tumor necrosis factor receptor gene family. J. Immunol. 147, 3165–3169 (1991).

    PubMed  CAS  Google Scholar 

  123. De Jong, R. et al. The CD27- subset of peripheral blood memory CD4+ lymphocytes contains functionally differentiated T lymphocytes that develop by persistent antigenic stimulation in vivo. Eur. J. Immunol. 22, 993–999 (1992).

    Article  PubMed  Google Scholar 

  124. Ferrando-Martinez, S., Ruiz-Mateos, E. & Leal, M. CD27 and CCR7 expression on naive T cells, are both necessary? Immunol. Lett. 127, 157–158 (2010).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  127. Rufer, N. et al. Ex vivo characterization of human CD8+ T subsets with distinct replicative history and partial effector functions. Blood 102, 1779–1787 (2003).

    Article  PubMed  CAS  Google Scholar 

  128. Schiott, A., Lindstedt, M., Johansson-Lindbom, B., Roggen, E. & Borrebaeck, C. A. CD27- CD4+ memory T cells define a differentiated memory population at both the functional and transcriptional levels. Immunology 113, 363–370 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Borthwick, N. J. et al. Lymphocyte activation in HIV-1 infection. II. Functional defects of CD28- T cells. AIDS 8, 431–441 (1994).

    Article  PubMed  CAS  Google Scholar 

  130. Fagnoni, F. F. et al. Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians. Immunology 88, 501–507 (1996).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Posnett, D. N., Sinha, R., Kabak, S. & Russo, C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to “benign monoclonal gammapathy”. J. Exp. Med. 179, 609–618 (1994).

    Article  PubMed  CAS  Google Scholar 

  132. Saukkonen, J. J., Kornfeld, H. & Berman, J. S. Expansion of a CD8+CD28- cell population in the blood and lung of HIV-positive patients. J. Acquir. Immune Def. Syndr. 6, 1194–1204 (1993).

    CAS  Google Scholar 

  133. Sfikakis, P. P. et al. CD28 expression on T cell subsets in vivo and CD28-mediated T cell response in vitro in patients with rheumatoid arthritis. Arthritis Rheum. 38, 649–654 (1995).

    Article  PubMed  CAS  Google Scholar 

  134. Strioga, M., Pasukoniene, V. & Characiejus, D. CD8+CD28- and CD8+CD57+ T cells and their role in health and disease. Immunology 134, 17–32 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors apologize to those colleagues whose relevant work was not included in this Review owing to space constraints. The authors thank R. de Boer, M. Hazenberg and L. Meyaard for critically reading the manuscript and for helpful comments and A. Boltjes for support with the figures.

Reviewer information

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

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Authors and Affiliations

  1. Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands

    Theo van den Broek, José A. M. Borghans & Femke van Wijk

  2. Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, Netherlands

    Theo van den Broek

  3. Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Theo van den Broek

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  1. Theo van den Broek
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  3. Femke van Wijk
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T.v.d.B., J.A.M.B. and F.v.W. wrote the manuscript and contributed to reviewing the literature and the review and editing of this article.

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Correspondence to Femke van Wijk.

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Glossary

Lymphopenia

The condition of having an abnormally low level of lymphocytes in the circulation.

Haematopoietic stem cell transplantation

(HSCT). Treatment of recipients with irradiation and/or chemotherapy followed by the infusion of cells containing haematopoietic stem and progenitor cells with or without immune cells derived from individuals of the same species.

Homeostatic proliferation

This term can refer to two different phenomena: the steady-state maintenance of T cells through self-renewal (minimal division) and the process by which T cells in lymphopenic conditions rapidly proliferate to reconstitute the T cell pool, also called lymphopenia-induced proliferation.

Virtual memory T cells

Antigen-inexperienced memory-phenotype T cells, which may be induced by T cell receptor cross reactivity, low-affinity peptide and/or MHC ligands and certain cytokines.

Mature naive T cells

Naive T cells that have matured in secondary lymphoid organs following thymic egress and are no longer recent thymic emigrants.

T cell receptor excision circles

(TRECs). Small, stable circles of DNA excised during T cell receptor gene rearrangement in the thymus.

Simpson’s diversity index

A measure of diversity that takes into account the number of clones present, as well as the relative abundance of each clone.

Repertoire skewedness

The extent to which a repertoire deviates from a situation where all clones occur equally frequently.

Thymic output

The amount of T cells that successfully exit the thymus into the periphery after intrathymic selection.

Graft-versus-host disease

(GVHD). An inflammatory complication following the transplantation of stem cells or organs to a genetically different person caused by donor immune cells that recognize the recipient’s cells and tissues as foreign.

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van den Broek, T., Borghans, J.A.M. & van Wijk, F. The full spectrum of human naive T cells. Nat Rev Immunol 18, 363–373 (2018). https://doi.org/10.1038/s41577-018-0001-y

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