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the unique TSCM population but also shows that these cells have high self-renewal capacity and therapeutic efficacy in a xenograft mouse model of antitumor adoptive cell therapy.

Like naive T cells, the newly discovered TSCM cells express CD45RA, CCR7, CD62L and inter-leukin-7 receptor α (IL-7Rα). However, unlike naive cells, the TSCM cells also express CD95, IL-2Rβ, CXCR3 and higher levels of lympho-cyte function–associated antigen-1, have under-gone several rounds of cell division, and show rapid cytokine production in response to T cell receptor stimulation. On the basis of these char-acteristics, it can be envisaged that TSCM cells

One of immunologists’ favorite exercises is to dissect the heterogeneity of immune cells through their surface marker expression patterns. This is not a trivial pursuit, as this approach has led to fundamental discoveries in many areas, from T and B cell development to immunological memory.

The ability to remember and respond more robustly against a second encounter with a pathogen is a fundamental property of the adaptive immune system that is carried out by expanded and differentiated clones of memory T and B cells, and it forms the basis of vaccina-tion. The identification of such memory cells and of the mechanisms that maintain these cells for a lifetime is not only of basic interest but also of practical relevance for the develop-ment of vaccines to target intracellular patho-gens and cancer.

A seminal discovery in the field of immu-nological memory was that the full-length form of the protein tyrosine phosphatase CD45, CD45RA, is expressed on the surface of human naive T cells, whereas the shorter form, CD45R0, is expressed on antigen- experienced memory T cells and their descendants1. Subsequent studies identified two functional subsets within CD45R0+ memory T cells: cen-tral memory T cells (TCM cells), which express the lymph node homing receptors CCR7 and CD62 ligand (CD62L) and have limited effec-tor function but high proliferative capacity, and effector memory T cells (TEM cells), which lack CCR7 and CD62L and show immediate effec-tor function in peripheral tissues2. By analogy with other cellular systems, it was proposed that immunological memory is maintained by

cells with stem-like properties and that these stem-like cells reside within the central memory pool, on the basis of the observation that TCM cells have higher proliferative and reconstitution capacity as compared to TEM cells3,4.

Building on their previous identification of an elusive subset of memory stem cells (TSCM cells) in mice5, in this issue of Nature Medicine Gattinoni et al.6 now report these cells are also present in humans. The human TSCM cells are ‘disguised’ as naive, as they express CD4RA and several other markers characteristic of naive T cells (Fig. 1). This study not only identifies a combination of markers that precisely define

Federica Sallusto and Antonio Lanzavecchia

are at the Institute for Research in Biomedicine,

Bellinzona, Switzerland.

e-mail: federica.sallusto@irb.unisi.ch or

lanzavecchia@irb.unisi.ch

Memory in disguiseFederica Sallusto & Antonio Lanzavecchia

Memory T cells can be maintained for a lifetime, but the underlying mechanism has been hard to pin down. A new study identifies a subset of memory T cells with stem cell properties in humans and shows that these cells mediate a superior antitumor response in a mouse model of adoptive T cell therapy (pages 1290–1297).

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Figure 1 During an immune response, naive T cells (TN) are primed by antigen-presenting cells (APCs) in secondary lymphoid organs. Depending on the strength and quality of stimulatory signals, proliferating T cells progress along a differentiation pathway, losing naive and acquiring effector properties. When antigen is eliminated, a range of primed T cells is rescued as memory T cells. Gattinoni et al.6 have identified a previously unknown memory T cell type that is distinct from the previously characterized TCM and TEM cells. TSCM cells are less differentiated and share several markers, including CD45RA, with the naive T cells. TSCM cells self-renew and differentiate in response to cytokines (dotted black arrows) or antigen (solid black arrows) and, in adoptive transfer experiments, have the highest reconstitution and antitumor capacity.

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circulate preferentially through lymph nodes and mucosal lymphoid organs, and at these sites they could undergo secondary responses, which may be facilitated by increased cell adhesion and responsiveness to chemokines. Notably, the authors show that the CD8+ TSCM subset contains stable T cell clones specific for viral antigens to which the donor is immune6. Additionally, they find that the same clones are also present within TCM and TEM subsets, indi-cating that the whole spectrum of phenotypes and functions characteristic of memory T cells can be reflected within a single expanded clone originating from a naive T cell (Fig. 1).

A key property of stem cells is the capacity to maintain their pool while generating large num-bers of differentiated cells. Gattinoni et al.6 show that in response to stimulation with antibody to CD3 or with IL-15, which represent in vitro surrogates of antigen-driven and homeostatic expansion, respectively, CD8+ TSCM cells undergo numerous cell divisions and produce TCM- and TEM-like cells, whereas a large fraction of proliferating cells retain the TSCM phenotype (Fig. 1). A substantial but lower degree of self-renewing capacity was also observed in the TCM subset, consistent with previous reports7. These findings6,7 suggest that, as in the hematopoietic system, there may be different hierarchies of memory stem cells, which reflect a progressive commitment to the final differentiation state.

The notion of a hierarchical system of memory T cells is supported by an extensive gene expres-sion analysis on isolated CD8+ memory T cell subsets carried out by Gattinoni et al.6. The authors found progressive changes from naive to TSCM, TCM and TEM cells that differed in the expression of 75, 157 and 226 transcripts, respec-tively. Notably, expression of genes encoding transcription factors that inhibit T cell activation

and differentiation and promote cellular quies-cence (such as lymphoid enhancer–binding factor 1 and forkhead box P1) progressively decreased from naive, to TSCM, TCM and TEM cells, whereas expression of the majority of genes associated with effector function (such as those encoding the transcription factors eomesoder-min and T-box 21 and for the cytotoxic mole-cules granzyme A and perforin) progressively increased in the same order. The changes in gene expression that accompany the development of memory CD8+ T cells are likely to be maintained during homeostatic cell division by epigenetic mechanisms, in analogy to what happens during development in the hematopoietic system. The identification of such mechanisms and of puta-tive cell-fate–determining transcription factors that may direct TSCM differentiation represents an interesting area of future investigation.

There has been an active debate about the lineage relationship of CD4+ and CD8+ TCM and TEM subsets and the point at which these subsets emerge during the immune response8,9. Both the gene expression analysis and the in vitro differentiation experiments performed by Gattinoni et al.6 are consistent with the view that T cell stimulation drives the cells down a linear TSCM to TCM to TEM differentiation path-way10. How TSCM cells are formed and when they emerge during the immune response are questions that remain to be addressed.

To explore the therapeutic potential of human TSCM cells, the authors stimulated human CD8+ T cells in vitro with antibodies to CD3 and CD28 in the presence of a pharmacological activator of Wnt signaling that they previously found to favor the generation of mouse TSCM cells5,6. They went on to show that, after transduction with a lentiviral vector encoding an antitumor T cell receptor, TSCM cells generated in this

way are much more effective compared to TCM or TEM cells in controlling tumor burden in a mouse xenograft tumor model. These findings therefore represent an important step forward for developing new strategies for adoptive cell therapy that can confer long-term protection against pathogens or cancer.

It can be anticipated that the findings of Gattinoni et al.6 will open new avenues for the identification of methods to expand TSCM cells in vivo. Recent studies in mice have shown that generation of memory T cells can be enhanced by pharmacological inhibition of mammalian target of rapamycin or by stimulation of fatty acid metabolism11,12. It will be interesting to determine whether the metabolic control of T cell priming enhances the generation of TSCM cells. Undoubtedly, the availability of surface markers for human TSCM cells will greatly facilitate research in the field of memory and protective immunity and its translation to the development of next-generation vaccines.

COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests.

1. Merkenschlager, M., Terry, L., Edwards, R. & Beverley, P.C. Eur. J. Immunol. 18, 1653–1661 (1988).

2. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Nature 401, 708–712 (1999).

3. Fearon, D.T., Manders, P. & Wagner, S.D. Science 293, 248–250 (2001).

4. Lanzavecchia, A. & Sallusto, F. Nat. Rev. Immunol. 2, 982–987 (2002).

5. Gattinoni, L. et al. Nat. Med. 15, 808–813 (2009).6. Gattinoni, L. et al. Nat. Med. 17, 1290–1297 (2011).7. Geginat, J., Lanzavecchia, A. & Sallusto, F. Blood 101,

4260–4266 (2003).8. Antia, R., Ganusov, V.V. & Ahmed, R. Nat. Rev.

Immunol. 5, 101–111 (2005).9. Pepper, M. & Jenkins, M.K. Nat. Immunol. 12,

467–471 (2011).10. Lanzavecchia, A. & Sallusto, F. Science 290, 92–97

(2000).11. Araki, K. et al. Nature 460, 108–112 (2009).12. Pearce, E.L. et al. Nature 460, 103–107 (2009).

negative for estrogen, progesterone receptors and HER2neu. These ‘triple- negative’ tumors are particularly difficult to treat3. Moreover, response to DNA-damaging therapy is highly influenced by the BRCA1 status of the tumors3. Thus, BRCA1 mutation carriers can benefit from prophylactic methods as well as from customized treatment options.

Women with a family history of breast and/or ovarian cancer have plenty of reasons to undergo genetic testing for mutations in BRCA1, as it

is the major locus for predisposition to these cancers, and inactivating germline mutations are present in ~40% of families with multiple cases of breast cancer1. BRCA1 is involved in a number of cellular processes, such as DNA damage repair, transcriptional regulation and control of cell cycle progression2. BRCA1-linked breast cancers tend to have early onset and be

Aneliya Velkova and Alvaro N.A. Monteiro are at

the Cancer Epidemiology Program at H. Lee Moffitt

Cancer Center, Tampa, Florida, USA.

e-mail: alvaro.monteiro@moffitt.org

Epigenetic tumor suppression by BRCA1Aneliya Velkova & Alvaro N A Monteiro

BRCA1 germline mutations lead to an increased risk of breast and ovarian cancer, but the mechanisms by which the product of this gene functions as a tumor suppressor have remained elusive. Now, analysis of a missense BRCA1 variant shows that it can epigenetically regulate an miRNA implicated in cancer, providing new mechanistic insights (pages 1275–1282).

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