Review Article | Published:

T memory stem cells in health and disease

Nature Medicine volume 23, pages 1827 (2017) | Download Citation

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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References

  1. 1.

    Peloponnesian Warre (Charles Harper, London, 1676).

  2. 2.

    , , & From vaccines to memory and back. Immunity 33, 451–463 (2010).

  3. 3.

    , , & The precursors of memory: models and controversies. Nat. Rev. Immunol. 9, 662–668 (2009).

  4. 4.

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

  5. 5.

    , , & Human cytotoxic T-cell memory: long-lived responses to vaccinia virus. J. Virol. 70, 2627–2631 (1996).

  6. 6.

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

  7. 7.

    , & Arrested differentiation, the self-renewing memory lymphocyte, and vaccination. Science 293, 248–250 (2001).

  8. 8.

    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).

  9. 9.

    , , , & Cutting edge: Asymmetric memory T cell division in response to rechallenge. J. Immunol. 188, 4145–4148 (2012).

  10. 10.

    , & Paths to stemness: building the ultimate antitumour T cell. Nat. Rev. Cancer 12, 671–684 (2012).

  11. 11.

    , , & Single-cell technologies for monitoring immune systems. Nat. Immunol. 15, 128–135 (2014).

  12. 12.

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

  13. 13.

    , , , & Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

  14. 14.

    , , , & Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat. Med. 11, 1299–1305 (2005).

  15. 15.

    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).

  16. 16.

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

  17. 17.

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

  18. 18.

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

  19. 19.

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

  20. 20.

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

  21. 21.

    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).

  22. 22.

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

  23. 23.

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

  24. 24.

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

  25. 25.

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

  26. 26.

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

  27. 27.

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

  28. 28.

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

  29. 29.

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

  30. 30.

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

  31. 31.

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

  32. 32.

    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).

  33. 33.

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

  34. 34.

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

  35. 35.

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

  36. 36.

    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).

  37. 37.

    , , & 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).

  38. 38.

    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).

  39. 39.

    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).

  40. 40.

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

  41. 41.

    , , , & 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).

  42. 42.

    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).

  43. 43.

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

  44. 44.

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

  45. 45.

    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).

  46. 46.

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

  47. 47.

    et al. The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci. Immunol. (2016).

  48. 48.

    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).

  49. 49.

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

  50. 50.

    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).

  51. 51.

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

  52. 52.

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

  53. 53.

    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).

  54. 54.

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

  55. 55.

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

  56. 56.

    , & Molecular regulation of effector and memory T cell differentiation. Nat. Immunol. 15, 1104–1115 (2014).

  57. 57.

    , & 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).

  58. 58.

    et al. Rapid and continued T cell differentiation into long-term effector and memory stem cells in vaccinated melanoma patients. Clin. Cancer Res. (2016).

  59. 59.

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

  60. 60.

    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).

  61. 61.

    & 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).

  62. 62.

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

  63. 63.

    , & Human memory T cells: generation, compartmentalization and homeostasis. Nat. Rev. Immunol. 14, 24–35 (2014).

  64. 64.

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

  65. 65.

    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).

  66. 66.

    , & Differentiation, expansion, and homeostasis of autoreactive T cells in type 1 diabetes mellitus. Curr. Diab. Rep. 9, 113–118 (2009).

  67. 67.

    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).

  68. 68.

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

  69. 69.

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

  70. 70.

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

  71. 71.

    & Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

  72. 72.

    , & Adoptive cellular therapy: a race to the finish line. Sci. Transl. Med. 7, 280ps7 (2015).

  73. 73.

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

  74. 74.

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

  75. 75.

    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).

  76. 76.

    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).

  77. 77.

    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).

  78. 78.

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

  79. 79.

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

  80. 80.

    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).

  81. 81.

    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).

  82. 82.

    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).

  83. 83.

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

  84. 84.

    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).

  85. 85.

    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).

  86. 86.

    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).

  87. 87.

    , , , & Role of memory T cell subsets for adoptive immunotherapy. Semin. Immunol. 28, 28–34 (2016).

  88. 88.

    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).

  89. 89.

    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).

  90. 90.

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

  91. 91.

    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).

  92. 92.

    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).

  93. 93.

    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).

  94. 94.

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

  95. 95.

    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).

  96. 96.

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

  97. 97.

    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).

  98. 98.

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

  99. 99.

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

  100. 100.

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

  101. 101.

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

  102. 102.

    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).

  103. 103.

    , , & Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Sci. Transl. Med. 8, 320ra3 (2016).

  104. 104.

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

  105. 105.

    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).

  106. 106.

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

  107. 107.

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

  108. 108.

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

  109. 109.

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

  110. 110.

    , & Pharmacologic induction of CD8+ T cell memory: better living through chemistry. Sci. Transl. Med. 1, 11ps12 (2009).

  111. 111.

    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).

  112. 112.

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

  113. 113.

    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).

  114. 114.

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

  115. 115.

    , & Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? J. Immunother. 35, 651–660 (2012).

  116. 116.

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

  117. 117.

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

  118. 118.

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

  119. 119.

    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).

  120. 120.

    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).

  121. 121.

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

  122. 122.

    , , , & Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J. Immunol. 168, 4827–4831 (2002).

  123. 123.

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

  124. 124.

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

  125. 125.

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

  126. 126.

    , , , & An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity 35, 792–805 (2011).

  127. 127.

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

  128. 128.

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

  129. 129.

    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).

  130. 130.

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

  131. 131.

    & Moving T memory stem cells to the clinic. Blood 121, 567–568 (2013).

  132. 132.

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

  133. 133.

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

  134. 134.

    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).

  135. 135.

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

  136. 136.

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

  137. 137.

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

  138. 138.

    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).

  139. 139.

    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).

  140. 140.

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

  141. 141.

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

  142. 142.

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

  143. 143.

    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).

  144. 144.

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

  145. 145.

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

  146. 146.

    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).

  147. 147.

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

  148. 148.

    , , & 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).

  149. 149.

    , , & Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013).

  150. 150.

    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).

  151. 151.

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

  152. 152.

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

  153. 153.

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

  154. 154.

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

  155. 155.

    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).

  156. 156.

    , , & Bone marrow is a preferred site for homeostatic proliferation of memory CD8 T cells. J. Immunol. 174, 1269–1273 (2005).

  157. 157.

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

  158. 158.

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

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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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  1. Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Luca Gattinoni
  2. Department of Oncology, Ludwig Cancer Research, Lausanne University Hospital, Lausanne, Switzerland.

    • Daniel E Speiser
  3. Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Mathias Lichterfeld
  4. Experimental Hematology Unit, Division of Immunology Transplantation and Infectious Diseases, Leukemia Unit, San Raffaele Scientific Institute, Milan, Italy.

    • Chiara Bonini
  5. Hematology Department, Vita Salute San Raffaele University, Milan, Italy.

    • Chiara Bonini

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

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https://doi.org/10.1038/nm.4241

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