Immunological memory is thought to depend on a stem cell–like, self-renewing population of lymphocytes capable of differentiating into effector cells in response to antigen re-exposure. Here we describe a long-lived human memory T cell population that has an enhanced capacity for self-renewal and a multipotent ability to derive central memory, effector memory and effector T cells. These cells, specific to multiple viral and self-tumor antigens, were found within a CD45RO−, CCR7+, CD45RA+, CD62L+, CD27+, CD28+ and IL-7Rα+ T cell compartment characteristic of naive T cells. However, they expressed large amounts of CD95, IL-2Rβ, CXCR3, and LFA-1, and showed numerous functional attributes distinctive of memory cells. Compared with known memory populations, these lymphocytes had increased proliferative capacity and more efficiently reconstituted immunodeficient hosts, and they mediated superior antitumor responses in a humanized mouse model. The identification of a human stem cell–like memory T cell population is of direct relevance to the design of vaccines and T cell therapies.
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Wakim, L.M. & Bevan, M.J. From the thymus to longevity in the periphery. Curr. Opin. Immunol. 22, 274–278 (2010).
Kim, P.S. & Ahmed, R. Features of responding T cells in cancer and chronic infection. Curr. Opin. Immunol. 22, 223–230 (2010).
Klebanoff, C.A., Gattinoni, L. & Restifo, N.P. CD8+ T-cell memory in tumor immunology and immunotherapy. Immunol. Rev. 211, 214–224 (2006).
Fearon, D.T., Manders, P. & Wagner, S.D. Arrested differentiation, the self-renewing memory lymphocyte, and vaccination. Science 293, 248–250 (2001).
Stemberger, C. et al. Stem cell-like plasticity of naive and distinct memory CD8+ T cell subsets. Semin. Immunol. 21, 62–68 (2009).
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).
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).
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).
Gattinoni, L. et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat. Med. 15, 808–813 (2009).
Neuenhahn, M. & Busch, D.H. The quest for CD8+ memory stem cells. Immunity 31, 702–704 (2009).
Turtle, C.J., Swanson, H.M., Fujii, N., Estey, E.H. & Riddell, S.R. A distinct subset of self-renewing human memory CD8+ T cells survives cytotoxic chemotherapy. Immunity 31, 834–844 (2009).
Dusseaux, M. et al. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117, 1250–1259 (2011).
Schenkel, J.M., Zloza, A., Li, W., Narasipura, S.D. & Al-Harthi, L. β-catenin signaling mediates CD4 expression on mature CD8+ T cells. J. Immunol. 185, 2013–2019 (2010).
Gattinoni, L., Ji, Y. & Restifo, N.P. Wnt/β-catenin signaling in T-cell immunity and cancer immunotherapy. Clin. Cancer Res. 16, 4695–4701 (2010).
Gattinoni, L., Ji, Y. & Restifo, N.P. β-catenin does not regulate memory T cell phenotype. Reply. Nat. Med. 16, 514–515 (2010).
Appay, V., van Lier, R.A., Sallusto, F. & Roederer, M. Phenotype and function of human T lymphocyte subsets: consensus and issues. Cytometry A 73, 975–983 (2008).
De Rosa, S.C., Herzenberg, L.A., Herzenberg, L.A. & Roederer, M. 11-color, 13-parameter flow cytometry: identification of human naive T cells by phenotype, function, and T-cell receptor diversity. Nat. Med. 7, 245–248 (2001).
Douek, D.C. et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690–695 (1998).
Kambayashi, T., Assarsson, E., Lukacher, A.E., Ljunggren, H.G. & Jensen, P.E. Memory CD8+ T cells provide an early source of IFN-γ. J. Immunol. 170, 2399–2408 (2003).
Surh, C.D. & Sprent, J. Homeostatic T cell proliferation: how far can T cells be activated to self-ligands? J. Exp. Med. 192, F9–F14 (2000).
Prlic, M., Lefrancois, L. & Jameson, S.C. Multiple choices: regulation of memory CD8 T cell generation and homeostasis by interleukin (IL)-7 and IL-15. J. Exp. Med. 195, F49–F52 (2002).
Lugli, E. et al. Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates. Blood 116, 3238–3248 (2010).
Alanio, C., Lemaitre, F., Law, H.K., Hasan, M. & Albert, M.L. Enumeration of human antigen-specific naive CD8+ T cells reveals conserved precursor frequencies. Blood 115, 3718–3725 (2010).
Zippelius, A. et al. Thymic selection generates a large T cell pool recognizing a self-peptide in humans. J. Exp. Med. 195, 485–494 (2002).
Willinger, T., Freeman, T., Hasegawa, H., McMichael, A.J. & Callan, M.F. Molecular signatures distinguish human central memory from effector memory CD8 T cell subsets. J. Immunol. 175, 5895–5903 (2005).
Pearce, E.L. et al. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 302, 1041–1043 (2003).
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).
Rutishauser, R.L. et al. Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31, 296–308 (2009).
Feng, X. et al. Transcription factor Foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive T cells. Nat. Immunol. 12, 544–550 (2011).
Ogretmen, B. & Hannun, Y.A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer 4, 604–616 (2004).
Khan, J. et al. Gene expression profiling of alveolar rhabdomyosarcoma with cDNA microarrays. Cancer Res. 58, 5009–5013 (1998).
Oberdoerffer, S. et al. Regulation of CD45 alternative splicing by heterogeneous ribonucleoprotein, hnRNPLL. Science 321, 686–691 (2008).
Hinrichs, C.S. et al. Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy. Blood 117, 808–814 (2011).
Carpenito, C. et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc. Natl. Acad. Sci. USA 106, 3360–3365 (2009).
Gattinoni, L., Powell, D.J. Jr., Rosenberg, S.A. & Restifo, N.P. Adoptive immunotherapy for cancer: building on success. Nat. Rev. Immunol. 6, 383–393 (2006).
June, C.H. Adoptive T cell therapy for cancer in the clinic. J. Clin. Invest. 117, 1466–1476 (2007).
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).
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).
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).
Morgan, R.A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).
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).
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).
Boursalian, T.E., Golob, J., Soper, D.M., Cooper, C.J. & Fink, P.J. Continued maturation of thymic emigrants in the periphery. Nat. Immunol. 5, 418–425 (2004).
Zhao, C. & Davies, J.D. A peripheral CD4+ T cell precursor for naive, memory, and regulatory T cells. J. Exp. Med. 207, 2883–2894 (2010).
Song, K. et al. Characterization of subsets of CD4+ memory T cells reveals early branched pathways of T cell differentiation in humans. Proc. Natl. Acad. Sci. USA 102, 7916–7921 (2005).
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).
Beier, C.P. & Schulz, J.B. CD95/Fas in the brain–not just a killer. Cell Stem Cell 5, 128–130 (2009).
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).
Zhou, X. et al. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 33, 229–240 (2010).
Wirth, T.C. et al. Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8+ T cell differentiation. Immunity 33, 128–140 (2010).
Sallusto, F., Lanzavecchia, A., Araki, K. & Ahmed, R. From vaccines to memory and back. Immunity 33, 451–463 (2010).
Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).
Appay, V., Douek, D.C. & Price, D.A. CD8+ T cell efficacy in vaccination and disease. Nat. Med. 14, 623–628 (2008).
Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).
Pearce, E.L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).
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).
Price, D.A. et al. Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses. J. Exp. Med. 202, 1349–1361 (2005).
Roederer, M., Nozzi, J.L. & Nason, M.C. SPICE: exploration and analysis of post-cytometric complex multivariate datasets. Cytometry A 79, 167–174 (2011).
This research was supported by the Intramural Research Programs of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research and National Institute of Allergy and Infectious Diseases. We thank S.A. Rosenberg and J.R. Wunderlich for providing samples from HLA-A*0201 patients with melanoma; P. Scheinberg for providing HLA-A*0201 samples; M. Sabatino for coordinating phereses; B.J. Hill for assistance with the TREC assay; S.P. Perfetto, R. Nguyen, D.A. Ambrozak, A. Mixon and S. Farid for help with cell sorting; P.K. Chattopadhyay and J. Yu for antibody conjugation; and R.A. Seder and C.A. Klebanoff for critical review of the manuscript.
The authors declare no competing financial interests.
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