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T memory stem cells in health and disease

Abstract

T memory stem (TSCM) cells are a rare subset of memory lymphocytes endowed with the stem cell–like ability to self-renew and the multipotent capacity to reconstitute the entire spectrum of memory and effector T cell subsets. Cumulative evidence in mice, nonhuman primates and humans indicates that TSCM cells are minimally differentiated cells at the apex of the hierarchical system of memory T lymphocytes. Here we describe emerging findings demonstrating that TSCM cells, owing to their extreme longevity and robust potential for immune reconstitution, are central players in many physiological and pathological human processes. We also discuss how TSCM cell stemness could be leveraged therapeutically to enhance the efficacy of vaccines and adoptive T cell therapies for cancer and infectious diseases or, conversely, how it could be disrupted to treat TSCM cell driven and sustained diseases, such as autoimmunity, adult T cell leukemia and HIV-1.

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Figure 1: T cell stemness and TSCM cells: milestones and key discoveries.
Figure 2: Hierarchical model of human T cell differentiation.
Figure 3: TSCM-cell-based therapeutic interventions for human diseases.

References

  1. 1

    Thucydides & Hobbes, T. Peloponnesian Warre (Charles Harper, London, 1676).

    Google Scholar 

  2. 2

    Sallusto, F., Lanzavecchia, A., Araki, K. & Ahmed, R. From vaccines to memory and back. Immunity 33, 451–463 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Ahmed, R., Bevan, M.J., Reiner, S.L. & Fearon, D.T. The precursors of memory: models and controversies. Nat. Rev. Immunol. 9, 662–668 (2009).

    CAS  PubMed  Google Scholar 

  4. 4

    Restifo, N.P. & Gattinoni, L. Lineage relationship of effector and memory T cells. Curr. Opin. Immunol. 25, 556–563 (2013).

    CAS  PubMed  Google Scholar 

  5. 5

    Demkowicz, W.E. Jr., Littaua, R.A., Wang, J. & Ennis, F.A. Human cytotoxic T-cell memory: long-lived responses to vaccinia virus. J. Virol. 70, 2627–2631 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Hammarlund, E. et al. Duration of antiviral immunity after smallpox vaccination. Nat. Med. 9, 1131–1137 (2003).

    CAS  PubMed  Google Scholar 

  7. 7

    Fearon, D.T., Manders, P. & Wagner, S.D. Arrested differentiation, the self-renewing memory lymphocyte, and vaccination. Science 293, 248–250 (2001).

    CAS  PubMed  Google Scholar 

  8. 8

    Luckey, C.J. et al. Memory T and memory B cells share a transcriptional program of self-renewal with long-term hematopoietic stem cells. Proc. Natl. Acad. Sci. USA 103, 3304–3309 (2006).

    CAS  PubMed  Google Scholar 

  9. 9

    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  PubMed Central  Google Scholar 

  10. 10

    Gattinoni, L., Klebanoff, C.A. & Restifo, N.P. Paths to stemness: building the ultimate antitumour T cell. Nat. Rev. Cancer 12, 671–684 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Chattopadhyay, P.K., Gierahn, T.M., Roederer, M. & Love, J.C. Single-cell technologies for monitoring immune systems. Nat. Immunol. 15, 128–135 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    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 

  13. 13

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

    CAS  Google Scholar 

  14. 14

    Zhang, Y., Joe, G., Hexner, E., Zhu, J. & Emerson, S.G. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat. Med. 11, 1299–1305 (2005).

    CAS  PubMed  Google Scholar 

  15. 15

    Long, H.M. et al. MHC II tetramers visualize human CD4+ T cell responses to Epstein-Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response. J. Exp. Med. 210, 933–949 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Miller, J.D. et al. Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity 28, 710–722 (2008).

    CAS  PubMed  Google Scholar 

  17. 17

    Akondy, R.S. et al. The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response. J. Immunol. 183, 7919–7930 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Gattinoni, L. et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat. Med. 15, 808–813 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

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

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Lugli, E. et al. Identification, isolation and in vitro expansion of human and nonhuman primate T stem cell memory cells. Nat. Protoc. 8, 33–42 (2013).

    CAS  PubMed  Google Scholar 

  21. 21

    Di Benedetto, S. et al. Impact of age, sex and CMV-infection on peripheral T cell phenotypes: results from the Berlin BASE-II Study. Biogerontology 16, 631–643 (2015).

    CAS  PubMed  Google Scholar 

  22. 22

    Roederer, M. et al. The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis. Cell 161, 387–403 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Cieri, N. et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood 121, 573–584 (2013).

    CAS  PubMed  Google Scholar 

  24. 24

    Lugli, E. et al. Superior T memory stem cell persistence supports long-lived T cell memory. J. Clin. Invest. 123, 594–599 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Simons, B.D. & Clevers, H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145, 851–862 (2011).

    CAS  Google Scholar 

  26. 26

    Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).

    CAS  PubMed  Google Scholar 

  27. 27

    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 

  28. 28

    Gattinoni, L. Memory T cells officially join the stem cell club. Immunity 41, 7–9 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Gerlach, C. et al. Heterogeneous differentiation patterns of individual CD8+ T cells. Science 340, 635–639 (2013).

    CAS  PubMed  Google Scholar 

  30. 30

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

    CAS  PubMed  Google Scholar 

  31. 31

    Lanzavecchia, A. & Sallusto, F. Progressive differentiation and selection of the fittest in the immune response. Nat. Rev. Immunol. 2, 982–987 (2002).

    CAS  PubMed  Google Scholar 

  32. 32

    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 

  33. 33

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

    CAS  PubMed  Google Scholar 

  34. 34

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

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Oliveira, G. et al. Tracking genetically engineered lymphocytes long-term reveals the dynamics of T cell immunological memory. Sci. Transl. Med. 7, 317ra198 (2015).

    PubMed  Google Scholar 

  36. 36

    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).

    PubMed  Google Scholar 

  37. 37

    Fuertes Marraco, S.A., Soneson, C., Delorenzi, M. & Speiser, D.E. Genome-wide RNA profiling of long-lasting stem cell-like memory CD8 T cells induced by Yellow Fever vaccination in humans. Genom. Data 5, 297–301 (2015).

    PubMed  PubMed Central  Google Scholar 

  38. 38

    Biasco, L. et al. In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells. Sci. Transl. Med. 7, 273ra13 (2015).

    PubMed  Google Scholar 

  39. 39

    Xu, Y. et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood 123, 3750–3759 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Vigano, S. et al. Prolonged antiretroviral therapy preserves HIV-1-specific CD8 T cells with stem cell-like properties. J. Virol. 89, 7829–7840 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Axelsson-Robertson, R., Ju, J.H., Kim, H.Y., Zumla, A. & Maeurer, M. Mycobacterium tuberculosis-specific and MHC class I-restricted CD8+ T-cells exhibit a stem cell precursor-like phenotype in patients with active pulmonary tuberculosis. Int. J. Infect. Dis. 32, 13–22 (2015).

    CAS  PubMed  Google Scholar 

  42. 42

    Mateus, J. et al. Low frequency of circulating CD8+ T stem cell memory cells in chronic chagasic patients with severe forms of the disease. PLoS Negl. Trop. Dis. 9, e3432 (2015).

    PubMed  PubMed Central  Google Scholar 

  43. 43

    Ahmed, R. & Akondy, R.S. Insights into human CD8+ T-cell memory using the yellow fever and smallpox vaccines. Immunol. Cell Biol. 89, 340–345 (2011).

    CAS  PubMed  Google Scholar 

  44. 44

    Speiser, D.E. et al. T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion? Nat. Rev. Immunol. 14, 768–774 (2014).

    CAS  PubMed  Google Scholar 

  45. 45

    Utzschneider, D.T. et al. T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections. Immunity 45, 415–427 (2016).

    CAS  PubMed  Google Scholar 

  46. 46

    Im, S.J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Wu, T. et al. The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci. Immunol. http://dx.doi.org/10.1126/sciimmunol.aai8593 (2016).

  48. 48

    Ribeiro, S.P. et al. The CD8+ memory stem T cell (T(SCM)) subset is associated with improved prognosis in chronic HIV-1 infection. J. Virol. 88, 13836–13844 (2014).

    PubMed  PubMed Central  Google Scholar 

  49. 49

    Cartwright, E.K. et al. Divergent CD4+ T memory stem cell dynamics in pathogenic and nonpathogenic simian immunodeficiency virus infections. J. Immunol. 192, 4666–4673 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Klatt, N.R. et al. Limited HIV infection of central memory and stem cell memory CD4+ T cells is associated with lack of progression in viremic individuals. PLoS Pathog. 10, e1004345 (2014).

    PubMed  PubMed Central  Google Scholar 

  51. 51

    Cartwright, E.K. et al. Initiation of antiretroviral therapy restores CD4+ TSCM homeostasis in SIV-infected macaques. J. Virol. 90, 6699–6708 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Calascibetta, F. et al. Antiretroviral therapy in simian immunodeficiency virus-infected sooty mangabeys: implications for AIDS pathogenesis. J. Virol. 90, 7541–7551 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Speiser, D.E. et al. Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J. Clin. Invest. 115, 739–746 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Melero, I. et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat. Rev. Clin. Oncol. 11, 509–524 (2014).

    CAS  PubMed  Google Scholar 

  55. 55

    De Gregorio, E. & Rappuoli, R. Vaccines for the future: learning from human immunology. Microb. Biotechnol. 5, 149–155 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Chang, J.T., Wherry, E.J. & Goldrath, A.W. Molecular regulation of effector and memory T cell differentiation. Nat. Immunol. 15, 1104–1115 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Pham, N.L., Badovinac, V.P. & Harty, J.T. A default pathway of memory CD8 T cell differentiation after dendritic cell immunization is deflected by encounter with inflammatory cytokines during antigen-driven proliferation. J. Immunol. 183, 2337–2348 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Gannon, P. et al. Rapid and continued T cell differentiation into long-term effector and memory stem cells in vaccinated melanoma patients. Clin. Cancer Res. http://dx.doi.org/10.1158/1078-0432.CCR-16-1708 (2016).

  59. 59

    Park, C.O. & Kupper, T.S. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat. Med. 21, 688–697 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Mackay, L.K. et al. T-box transcription factors combine with the cytokines TGF-β and IL-15 to control tissue-resident memory T cell fate. Immunity 43, 1101–1111 (2015).

    CAS  PubMed  Google Scholar 

  61. 61

    Zhang, N. & Bevan, M.J. Transforming growth factor-β signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention. Immunity 39, 687–696 (2013).

    PubMed  PubMed Central  Google Scholar 

  62. 62

    Jameson, S.C. & Masopust, D. Diversity in T cell memory: an embarrassment of riches. Immunity 31, 859–871 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Farber, D.L., Yudanin, N.A. & Restifo, N.P. Human memory T cells: generation, compartmentalization and homeostasis. Nat. Rev. Immunol. 14, 24–35 (2014).

    CAS  PubMed  Google Scholar 

  64. 64

    Gattinoni, L. The dark side of T memory stem cells. Blood 125, 3519–3520 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Hosokawa, K. et al. Memory stem T cells in autoimmune disease: high frequency of circulating CD8+ memory stem cells in acquired aplastic anemia. J. Immunol. 196, 1568–1578 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Monti, P., Heninger, A.K. & Bonifacio, E. Differentiation, expansion, and homeostasis of autoreactive T cells in type 1 diabetes mellitus. Curr. Diab. Rep. 9, 113–118 (2009).

    CAS  PubMed  Google Scholar 

  67. 67

    Tabler, C.O. et al. CD4+ memory stem cells are infected by HIV-1 in a manner regulated in part by SAMHD1 expression. J. Virol. 88, 4976–4986 (2014).

    PubMed  PubMed Central  Google Scholar 

  68. 68

    Buzon, M.J. et al. HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat. Med. 20, 139–142 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Jaafoura, S. et al. Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4+ memory T cells. Nat. Commun. 5, 5407 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Nagai, Y. et al. T memory stem cells are the hierarchical apex of adult T-cell leukemia. Blood 125, 3527–3535 (2015).

    CAS  PubMed  Google Scholar 

  71. 71

    Rosenberg, S.A. & Restifo, N.P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    June, C.H., Riddell, S.R. & Schumacher, T.N. Adoptive cellular therapy: a race to the finish line. Sci. Transl. Med. 7, 280ps7 (2015).

    PubMed  Google Scholar 

  73. 73

    Dudley, M.E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Brentjens, R.J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra38 (2013).

    PubMed  PubMed Central  Google Scholar 

  75. 75

    Lee, D.W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015).

    CAS  PubMed  Google Scholar 

  76. 76

    Kochenderfer, J.N. et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 33, 540–549 (2015).

    CAS  PubMed  Google Scholar 

  77. 77

    Brudno, J.N. et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J. Clin. Oncol. 34, 1112–1121 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Maude, S.L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

    PubMed  PubMed Central  Google Scholar 

  79. 79

    Porter, D.L. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 7, 303ra139 (2015).

    PubMed  PubMed Central  Google Scholar 

  80. 80

    Robbins, P.F. et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin. Cancer Res. 21, 1019–1027 (2015).

    CAS  PubMed  Google Scholar 

  81. 81

    Robbins, P.F. et al. Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J. Immunol. 173, 7125–7130 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Pule, M.A. et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat. Med. 14, 1264–1270 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Rosenberg, S.A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Stevanovic´, S. et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J. Clin. Oncol. 33, 1543–1550 (2015).

    PubMed  PubMed Central  Google Scholar 

  86. 86

    Turtle, C.J. et al. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci. Transl. Med. 8, 355ra116 (2016).

    PubMed  PubMed Central  Google Scholar 

  87. 87

    Busch, D.H., Fräßle, S.P., Sommermeyer, D., Buchholz, V.R. & Riddell, S.R. Role of memory T cell subsets for adoptive immunotherapy. Semin. Immunol. 28, 28–34 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Zhou, J. et al. Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy. J. Immunol. 175, 7046–7052 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Huang, J. et al. Modulation by IL-2 of CD70 and CD27 expression on CD8+ T cells: importance for the therapeutic effectiveness of cell transfer immunotherapy. J. Immunol. 176, 7726–7735 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Louis, C.U. et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 118, 6050–6056 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Gattinoni, L. et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J. Clin. Invest. 115, 1616–1626 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Klebanoff, C.A. et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl. Acad. Sci. USA 102, 9571–9576 (2005).

    CAS  PubMed  Google Scholar 

  93. 93

    Hinrichs, C.S. et al. Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc. Natl. Acad. Sci. USA 106, 17469–17474 (2009).

    CAS  PubMed  Google Scholar 

  94. 94

    Wang, X. et al. Comparison of naive and central memory derived CD8+ effector cell engraftment fitness and function following adoptive transfer. OncoImmunology 5, e1072671 (2015).

    PubMed  PubMed Central  Google Scholar 

  95. 95

    Sommermeyer, D. et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 30, 492–500 (2016).

    CAS  PubMed  Google Scholar 

  96. 96

    Klebanoff, C.A. et al. Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice. Clin. Cancer Res. 17, 5343–5352 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Berger, C. et al. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J. Clin. Invest. 118, 294–305 (2008).

    CAS  PubMed  Google Scholar 

  98. 98

    Baitsch, L. et al. Exhaustion of tumor-specific CD8 T cells in metastases from melanoma patients. J. Clin. Invest. 121, 2350–2360 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Gros, A. et al. PD-1 identifies the patient-specific CD8 tumor-reactive repertoire infiltrating human tumors. J. Clin. Invest. 124, 2246–2259 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Lugli, E. et al. Subject classification obtained by cluster analysis and principal component analysis applied to flow cytometric data. Cytometry A 71, 334–344 (2007).

    PubMed  Google Scholar 

  101. 101

    Appay, V. et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat. Med. 8, 379–385 (2002).

    CAS  PubMed  Google Scholar 

  102. 102

    Mackall, C.L. et al. Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy. Blood 89, 3700–3707 (1997).

    CAS  PubMed  Google Scholar 

  103. 103

    Singh, N., Perazzelli, J., Grupp, S.A. & Barrett, D.M. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Sci. Transl. Med. 8, 320ra3 (2016).

    PubMed  Google Scholar 

  104. 104

    Turtle, C.J. et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Invest. 126, 2123–2138 (2016).

    PubMed  PubMed Central  Google Scholar 

  105. 105

    Wang, X. et al. Phase 1 studies of central-memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. Blood 24, 2980–2990 (2016).

    Google Scholar 

  106. 106

    Li, Q. et al. A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity. Immunity 34, 541–553 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Hinrichs, C.S. et al. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood 111, 5326–5333 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    van der Waart, A.B. et al. Inhibition of Akt signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy. Blood 124, 3490–3500 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Crompton, J.G. et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res. 75, 296–305 (2015).

    CAS  PubMed  Google Scholar 

  110. 110

    Gattinoni, L., Klebanoff, C.A. & Restifo, N.P. Pharmacologic induction of CD8+ T cell memory: better living through chemistry. Sci. Transl. Med. 1, 11ps12 (2009).

    PubMed  PubMed Central  Google Scholar 

  111. 111

    Davila, M.L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224ra25 (2014).

    PubMed  PubMed Central  Google Scholar 

  112. 112

    Grupp, S.A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Sabatino, M. et al. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood 128, 519–528 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Klebanoff, C.A. et al. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J. Clin. Invest. 126, 318–334 (2016).

    PubMed  Google Scholar 

  115. 115

    Klebanoff, C.A., Gattinoni, L. & Restifo, N.P. Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? J. Immunother. 35, 651–660 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Ding, Z.C. et al. IL-7 signaling imparts polyfunctionality and stemness potential to CD4+ T cells. OncoImmunology 5, e1171445 (2016).

    PubMed  PubMed Central  Google Scholar 

  117. 117

    Provasi, E. et al. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nat. Med. 18, 807–815 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Stemberger, C. et al. Lowest numbers of primary CD8+ T cells can reconstitute protective immunity upon adoptive immunotherapy. Blood 124, 628–637 (2014).

    CAS  PubMed  Google Scholar 

  119. 119

    Schmueck-Henneresse, M. et al. Peripheral blood-derived virus-specific memory stem T cells mature to functional effector memory subsets with self-renewal potency. J. Immunol. 194, 5559–5567 (2015).

    CAS  PubMed  Google Scholar 

  120. 120

    Terakura, S. et al. Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. Blood 119, 72–82 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Becker, T.C. et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J. Exp. Med. 195, 1541–1548 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Schluns, K.S., Williams, K., Ma, A., Zheng, X.X. & Lefrançois, L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J. Immunol. 168, 4827–4831 (2002).

    CAS  PubMed  Google Scholar 

  123. 123

    Yi, J.S., Du, M. & Zajac, A.J. A vital role for interleukin-21 in the control of a chronic viral infection. Science 324, 1572–1576 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Fröhlich, A. et al. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science 324, 1576–1580 (2009).

    PubMed  Google Scholar 

  125. 125

    Yi, J.S., Ingram, J.T. & Zajac, A.J. IL-21 deficiency influences CD8 T cell quality and recall responses following an acute viral infection. J. Immunol. 185, 4835–4845 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Cui, W., Liu, Y., Weinstein, J.S., Craft, J. & Kaech, S.M. An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity 35, 792–805 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    van der Windt, G.J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).

    CAS  PubMed  Google Scholar 

  128. 128

    Sukumar, M. et al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Invest. 123, 4479–4488 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Liu, L. et al. Novel CD4-based bispecific chimeric antigen receptor designed for enhanced anti-HIV potency and absence of HIV entry receptor activity. J. Virol. 89, 6685–6694 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Ali, A. et al. HIV-1-specific chimeric antigen receptors based on broadly neutralizing antibodies. J. Virol. 90, 6999–7006 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Gattinoni, L. & Restifo, N.P. Moving T memory stem cells to the clinic. Blood 121, 567–568 (2013).

    CAS  PubMed  Google Scholar 

  132. 132

    Kahn, M. Can we safely target the WNT pathway? Nat. Rev. Drug Discov. 13, 513–532 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Ramishetti, S. et al. Systemic gene silencing in primary T lymphocytes using targeted lipid nanoparticles. ACS Nano 9, 6706–6716 (2015).

    CAS  PubMed  Google Scholar 

  134. 134

    Zhou, J. et al. Selection, characterization and application of new RNA HIV gp 120 aptamers for facile delivery of Dicer substrate siRNAs into HIV infected cells. Nucleic Acids Res. 37, 3094–3109 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Tebas, P. et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N. Engl. J. Med. 370, 901–910 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Dragic, T. et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381, 667–673 (1996).

    CAS  Google Scholar 

  137. 137

    Scholz, G. et al. Modulation of mTOR signalling triggers the formation of stem cell-like memory T cells. EBioMedicine 4, 50–61 (2016).

    PubMed  PubMed Central  Google Scholar 

  138. 138

    Crompton, J.G. et al. Lineage relationship of CD8+ T cell subsets is revealed by progressive changes in the epigenetic landscape. Cell. Mol. Immunol. 13, 502–513 (2016).

    CAS  PubMed  Google Scholar 

  139. 139

    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 

  140. 140

    Lin, W.H. et al. Asymmetric PI3K signaling driving developmental and regenerative cell fate bifurcation. Cell Reports 13, 2203–2218 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Verbist, K.C. et al. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532, 389–393 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Pollizzi, K.N. et al. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8+ T cell differentiation. Nat. Immunol. 17, 704–711 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Jeannet, G. et al. Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory. Proc. Natl. Acad. Sci. USA 107, 9777–9782 (2010).

    CAS  PubMed  Google Scholar 

  144. 144

    Zhou, X. et al. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 33, 229–240 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Zhao, D.M. et al. Constitutive activation of Wnt signaling favors generation of memory CD8 T cells. J. Immunol. 184, 1191–1199 (2010).

    CAS  PubMed  Google Scholar 

  146. 146

    Boudousquié, C. et al. Differences in the transduction of canonical Wnt signals demarcate effector and memory CD8 T cells with distinct recall proliferation capacity. J. Immunol. 193, 2784–2791 (2014).

    Google Scholar 

  147. 147

    Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Rao, R.R., Li, Q., Odunsi, K. & Shrikant, P.A. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression |of transcription factors T-bet and Eomesodermin. Immunity 32, 67–78 (2010).

    PubMed  PubMed Central  Google Scholar 

  149. 149

    Pearce, E.L., Poffenberger, M.C., Chang, C.H. & Jones, R.G. Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013).

    PubMed  PubMed Central  Google Scholar 

  150. 150

    van der Windt, G.J. et al. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc. Natl. Acad. Sci. USA 110, 14336–14341 (2013).

    CAS  PubMed  Google Scholar 

  151. 151

    Sukumar, M. et al. Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. Cell Metab. 23, 63–76 (2016).

    CAS  PubMed  Google Scholar 

  152. 152

    Buck, M.D. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63–76 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Morrison, S.J. & Spradling, A.C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598–611 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Di Rosa, F. Two niches in the bone marrow: a hypothesis on life-long T cell memory. Trends Immunol. 37, 503–512 (2016).

    CAS  PubMed  Google Scholar 

  155. 155

    Alp, Ö.S. et al. Memory CD8+ T cells colocalize with IL-7+ stromal cells in bone marrow and rest in terms of proliferation and transcription. Eur. J. Immunol. 45, 975–987 (2015).

    Google Scholar 

  156. 156

    Becker, T.C., Coley, S.M., Wherry, E.J. & Ahmed, R. Bone marrow is a preferred site for homeostatic proliferation of memory CD8 T cells. J. Immunol. 174, 1269–1273 (2005).

    CAS  PubMed  Google Scholar 

  157. 157

    Mazo, I.B. et al. Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells. Immunity 22, 259–270 (2005).

    CAS  PubMed  Google Scholar 

  158. 158

    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).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research (ZIABC011480), the 2014 US National Institutes of Health (NIH) Bench-to-Bedside Award, (to L.G.) NIH grants AI098487, AI106468, AI114235, AI117841, AI120008, AI124776 (to M.L.), the Cancer Research Institute (N.Y.), the Ludwig Cancer Research (N.Y.), the Swiss Cancer League (3507-08-2014), the Swiss National Science Foundation (320030_152856, CRSII3_160708), the SwissTransMed (KIP 18) (to D.E.S.), the Italian Association for Cancer Research and the SUPERSIST (EU-FP7 project) (to C.B.).

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Correspondence to Luca Gattinoni or Daniel E Speiser or Mathias Lichterfeld or Chiara Bonini.

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Gattinoni, L., Speiser, D., Lichterfeld, M. et al. T memory stem cells in health and disease. Nat Med 23, 18–27 (2017). https://doi.org/10.1038/nm.4241

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