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. 2013 Jan 24;121(4):573-84.
doi: 10.1182/blood-2012-05-431718. Epub 2012 Nov 15.

IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors

Nicoletta Cieri  1 , Barbara Camisa, Fabienne Cocchiarella, Mattia Forcato, Giacomo Oliveira, Elena Provasi, Attilio Bondanza, Claudio Bordignon, Jacopo Peccatori, Fabio Ciceri, Maria Teresa Lupo-Stanghellini, Fulvio Mavilio, Anna Mondino, Silvio Bicciato, Alessandra Recchia, Chiara Bonini
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Free article

IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors

Nicoletta Cieri et al. Blood. .
Free article

Abstract

Long-living memory stem T cells (T(SCM)) with the ability to self-renew and the plasticity to differentiate into potent effectors could be valuable weapons in adoptive T-cell therapy against cancer. Nonetheless, procedures to specifically target this T-cell population remain elusive. Here, we show that it is possible to differentiate in vitro, expand, and gene modify in clinically compliant conditions CD8(+) T(SCM) lymphocytes starting from naive precursors. Requirements for the generation of this T-cell subset, described as CD62L(+)CCR7(+)CD45RA(+)CD45R0(+)IL-7Rα(+)CD95(+), are CD3/CD28 engagement and culture with IL-7 and IL-15. Accordingly, T(SCM) accumulates early after hematopoietic stem cell transplantation. The gene expression signature and functional phenotype define this population as a distinct memory T-lymphocyte subset, intermediate between naive and central memory cells. When transplanted in immunodeficient mice, gene-modified naive-derived T(SCM) prove superior to other memory lymphocytes for the ability to expand and differentiate into effectors able to mediate a potent xenogeneic GVHD. Furthermore, gene-modified T(SCM) are the only T-cell subset able to expand and mediate GVHD on serial transplantation, suggesting self-renewal capacity in a clinically relevant setting. These findings provide novel insights into the origin and requirements for T(SCM) generation and pave the way for their clinical rapid exploitation in adoptive cell therapy.

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