A human memory T cell subset with stem cell–like properties

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Abstract

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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Figure 1: Identification of TSCM cells in human blood.
Figure 2: TSCM cells possess attributes of conventional memory T cells.
Figure 3: TSCM cells represent a distinct, less-differentiated T cell memory subset.
Figure 4: Enhanced self-renewal and multipotency of TSCM cells.
Figure 5: Increased proliferative capacity, survival and antitumor activity of TSCM cells.

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Acknowledgements

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.

Author information

L.G., E.L., Y.J., Z.P., C.M.P., J.R.A., Z.Y. and C.C. carried out experiments; L.G., E.L., Y.J., Z.P., C.M.P. and J.R.A. analyzed experiments; L.G., E.L., C.M.P., E.W., D.C.D., D.A.P., C.H.J., F.M.M., M.R. and N.P.R. designed experiments; E.G., M.F.Q. and D.A.P. contributed reagents; E.L. and M.R. edited the manuscript; and L.G. and N.P.R. wrote the manuscript.

Correspondence to Luca Gattinoni or Nicholas P Restifo.

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