Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Nicoletta Cieri1,
  2. Barbara Camisa2,
  3. Fabienne Cocchiarella3,
  4. Mattia Forcato4,
  5. Giacomo Oliveira2,
  6. Elena Provasi2,
  7. Attilio Bondanza2,
  8. Claudio Bordignon5,
  9. Jacopo Peccatori6,
  10. Fabio Ciceri6,
  11. Maria Teresa Lupo-Stanghellini6,
  12. Fulvio Mavilio3,
  13. Anna Mondino7,
  14. Silvio Bicciato4,
  15. Alessandra Recchia3, and
  16. Chiara Bonini2,*
  1. 1 University Vita-Salute San Raffaele, Milan, Italy;
  2. 2 Experimental Hematology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, PIBIC, San Raffaele Scientific Institute, Milan, Italy;
  3. 3 Center for Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy;
  4. 4 Center for Genome Research, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy;
  5. 5 MolMed SpA, Milan, Italy;
  6. 6 Hematology and Bone Marrow Transplantation Unit, Department of Oncology, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy;
  7. 7 Lymphocyte activation Unit, Division of Immunology, Transplantation and Infectious Diseases, PIBIC, San Raffaele Scientific Institute, Milan, Italy
  1. * Corresponding author; email: bonini.chiara{at}


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 naïve 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 naïve and central memory cells. When transplanted in immunodeficient mice, gene-modified naïve-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 upon 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.

  • Submitted May 22, 2012.
  • Accepted October 25, 2012.