T memory space stem cells (TSCM) 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 subsets. city of Athens in 430 BC recounting that stem cell-like memory T cells7. Over the past decade, the realization that memory T cells share a core transcriptional signature with HSCs8 and display functional properties found in stem cells, such as the capacity to divide asymmetrically to generate cellular heterogeneity9, has further strengthened the view that T cells, akin to all somatic tissues, may be hierarchically organized and sustained by antigen-specific T memory stem cells10. In this Review, we outline emerging findings demonstrating that a subset of minimally differentiated memory T cells behave as antigen-specific adult stem cells. We also discuss recent evidence placing these T memory stem cells (TSCM) at center stage in many physiological and pathological human processes. Finally, we highlight ongoing efforts aiming either at harnessing the therapeutic potential of TSCM for adoptive immunotherapies or conversely at destabilizing the TSCM compartment to eliminate drug-resistant viral reservoirs or treat adult T-cell leukemia and autoimmune diseases. The conceptual work and key discoveries that have shaped this field of investigation are summarized in the Timeline. The discovery of TSCM cells Advances in multiparameter flow cytometry over the last 20 years have allowed us to dissect the heterogeneity of the T-cell compartment with ever-increasing precision11. In a seminal study, van Lier and colleagues identified human na?ve, memory, and effector T-cell subsets based on the combinatorial expression of CD27 and CD45RA, with na?ve cells expressing both substances, whereas effector and storage cells expressing just Compact disc27 or Compact disc45RA, respectively12. Subsequent function by Sallusto from na?ve precursors by activating the WNT–catenin signaling pathway using the WNT ligand, WNT3A, or inhibitors of glycogen synthase kinase-318. Translated to human beings, this plan provides allowed the identification of human KPT-330 TSCM19 recently. Similar with their murine counterparts, individual and nonhuman primate (NHP) TSCM are clonally extended cells expressing a generally na?ve-like phenotype together with a core of memory markers such as for example Compact disc95, CXCR3, IL-2R, CD11a19 and CD58,20. These cells represent a part of circulating T lymphocytes ( 2C3%). Oddly enough, the regularity of circulating TSCM KPT-330 will not vary with age group21 considerably, but it is apparently linked and heritable with one nucleotide KPT-330 polymorphisms at a hereditary locus formulated with Compact disc9522, recommending a potential function of FAS signaling in the legislation of TSCM homeostasis. TSCM display all of the determining properties of storage cells, including a diluted content material of TCR excision circles, the capability to proliferate and discharge inflammatory cytokines in response to antigen re-exposure quickly, and a reliance on IL-7 and IL-15 for homeostatic turnover19,23. Despite being distinct from na functionally?ve T cells, they talk about similar recirculation distribution and patterns seeing that evidenced by detailed compartmentalization research in NHP24. For example, TSCM are located even more abundantly in lymph nodes set alongside the spleen and bone tissue marrow and so are practically absent from DCHS2 peripheral mucosae24. Thus, TSCM represent a subset of minimally differentiated T cells characterized by phenotypic and functional properties bridging na?ve and conventional memory cells (Fig. 1). Open in a separate window Physique 1: Hierarchical model of human T-cell differentiation.Following antigen priming, na?ve T cells (TN) progressively differentiate into diverse memory T-cell subpopulations and ultimately into terminally differentiated effector T cells (TTE). T-cell subsets are distinguished by the combinatorial expression of the indicated surface markers. As TN progressively differentiate into TTE, they drop or acquire specific functional and metabolic characteristics. TSCM, T memory stem cell; TCM, central memory T cell; TEM, effector memory T cell; m, mitochondrial membrane potential. TSCM cells: Evidence of stemness The concept of stemness embraces the capacity both to self-renew and to generate the entire spectrum of more differentiated cells25. When the presence of a stem cell pool of memory T lymphocytes was initially postulated by Fearon and colleagues7, the authors pointed to TCM as putative T memory stem cells. This assumption was based on the evidence that TCM are less differentiated than TEM and effector cells, as shown by their longer telomeres and lower expression of perforin, granzymes and other effector molecules13. Furthermore, it was intuitive to presume that the pool of T memory stem cells should be confined in lymph nodes and supplementary lymphoid organs, and TCM had been, at that right time, the just antigen-experienced T cells recognized to exhibit CCR7 and Compact disc62L. The idea that.