title: IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors.
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.
authors.affiliation: University Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Cieri
authors.forename: Barbara
authors.initials: B
authors.lastname: Camisa
authors.forename: Fabienne
authors.initials: F
authors.lastname: Cocchiarella
authors.forename: Mattia
authors.initials: M
authors.lastname: Forcato
authors.forename: Giacomo
authors.initials: G
authors.lastname: Oliveira
authors.forename: Elena
authors.initials: E
authors.lastname: Provasi
authors.forename: Attilio
authors.initials: A
authors.lastname: Bondanza
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Jacopo
authors.initials: J
authors.lastname: Peccatori
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Lupo-Stanghellini
authors.forename: Fulvio
authors.initials: F
authors.lastname: Mavilio
authors.forename: Anna
authors.initials: A
authors.lastname: Mondino
authors.forename: Silvio
authors.initials: S
authors.lastname: Bicciato
authors.forename: Alessandra
authors.initials: A
authors.lastname: Recchia
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D019041:L-Selectin / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D019014:fas Receptor / Q000378:metabolism
chemical_list: D019409:Interleukin-15; D015851:Interleukin-7; D019014:fas Receptor; D019041:L-Selectin; D017493:Leukocyte Common Antigens