Key Points• T SCM lymphocytes are preferentially generated from naive precursors in vivo early after haploidentical HSCT.• T SCM represent relevant novel players in the diversification of immunological memory after haploidentical HSCT.Memory stem T cells (T SCM ) have been proposed as key determinants of immunologic memory. However, their exact contribution to a mounting immune response, as well as the mechanisms and timing of their in vivo generation, are poorly understood. We longitudinally tracked T SCM dynamics in patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), thereby providing novel hints on the contribution of this subset to posttransplant immune reconstitution in humans. We found that donor-derived T SCM are highly enriched early after HSCT. We showed at the antigenspecific and clonal level that T SCM lymphocytes can differentiate directly from naive precursors infused within the graft and that the extent of T SCM generation might correlate with interleukin 7 serum levels. In vivo fate mapping through T-cell receptor sequencing allowed defining the in vivo differentiation landscapes of human naive T cells, supporting the notion that progenies of single naive cells embrace disparate fates in vivo and highlighting T SCM as relevant novel players in the diversification of immunological memory after allogeneic HSCT. (Blood. 2015;125(18):2865-2874

Adoptive T cell therapy (ACT) is a rapidly evolving therapeutic approach designed to harness T cell specificity and function to fight diseases. Based on the evidence that T lymphocytes can mediate a potent anti-tumor response, initially ACT solely relied on the isolation, in vitro expansion, and infusion of tumor-infiltrating or circulating tumor-specific T cells. Although effective in a subset of cases, in the first ACT clinical trials several patients experienced disease progression, in some cases after temporary disease control. This evidence prompted researchers to improve ACT products by taking advantage of the continuously evolving gene engineering field and by improving manufacturing protocols, to enable the generation of effective and long-term persisting tumor-specific T cell products. Despite recent advances, several challenges, including prioritization of antigen targets, identification, and optimization of tumor-specific T cell receptors, in the development of tools enabling T cells to counteract the immunosuppressive tumor microenvironment, still need to be faced. This review aims at summarizing the major achievements, hurdles and possible solutions designed to improve the ACT efficacy and safety profile in the context of liquid and solid tumors.

Objective Memory stem T (Tscm) cells are long‐lived, self‐renewing T cells that play a relevant role in immunologic memory. This study was undertaken to investigate whether Tscm cells accumulate in rheumatoid arthritis (RA). Methods The polarization and differentiation profiles of circulating T cells were assessed by flow cytometry. Antigen‐specific T cells were characterized by staining with major histocompatibility complex class II tetramers. The T cell receptor (TCR) repertoire was analyzed by high‐throughput sequencing using an unbiased RNA‐based approach in CD4+ T cell subpopulations sorted by fluorescence‐activated cell sorting. Results We analyzed the dynamics of circulating Tscm cells (identified as CD45RA+CD62L+CD95+ T cells) by flow cytometry in 27 RA patients, 16 of whom were also studied during treatment with the anti–tumor necrosis factor (anti‐TNF) agent etanercept. Age‐matched healthy donors were used as controls. CD4+ Tscm cells were selectively and significantly expanded in RA patients in terms of frequency and absolute numbers, and significantly contracted upon anti‐TNF treatment. Expanded CD4+ Tscm cells displayed a prevalent Th17 phenotype and a skewed TCR repertoire in RA patients, with the 10 most abundant clones representing up to 53.7% of the detected sequences. CD4+ lymphocytes specific for a citrullinated vimentin (Cit‐vimentin) epitope were expanded in RA patients with active disease. Tscm cells accounted for a large fraction of Cit‐vimentin–specific CD4+ cells. Conclusion Our results indicate that Tscm cells, including expanded clones specific for relevant autoantigens, accumulate in RA patients not exposed to biologic agents, and might be involved in the natural history of the disease. Further analysis of Tscm cell dynamics in autoimmune disorders may have implications for the design and efficacy assessment of innovative therapies.