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

Nicoletta Cieri, 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

Research output: Contribution to journalArticle

Abstract

Long-living memory stem T cells (TSCM) 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+ TSCM 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, TSCM 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 TSCM 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 TSCM 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 TSCM generation and pave the way for their clinical rapid exploitation in adoptive cell therapy.

Original languageEnglish
Pages (from-to)573-584
Number of pages12
JournalBlood
Volume121
Issue number4
DOIs
Publication statusPublished - Jan 24 2013

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Cieri, N., Camisa, B., Cocchiarella, F., Forcato, M., Oliveira, G., Provasi, E., Bondanza, A., Bordignon, C., Peccatori, J., Ciceri, F., Lupo-Stanghellini, M. T., Mavilio, F., Mondino, A., Bicciato, S., Recchia, A., & Bonini, C. (2013). IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood, 121(4), 573-584. https://doi.org/10.1182/blood-2012-05-431718