title: Mimicking homeostatic proliferation in vitro generates T cells with high anti-tumor function in non-lymphopenic hosts.
abstract: CD8(+) T cells undergoing homeostatic proliferation (HP) in a lymphopenic environment acquire a central memory-like phenotype (CD44(+) CD62L(+) Ly6c(+)). Such cells are readily functional in vitro, with a strong capacity to secrete IFNγ and IL-2 and to lyse target cells upon antigen recognition. In vivo, these memory-like T cells display potent anti-tumor reactivity. When addressing whether these remarkable properties were "acquired" or dependent on sustained HP, we observed, for the first time, that memory-like T cells retained full anti-tumor functions even when removed from their lymphopenic environment and retransferred into non-lymphopenic P14/Rag2(-/-) recipients (where HP is prevented). Moreover, memory-like T cells were superior to in vitro expanded effector T cells. We next sought to determine the conditions required to reproduce such a potent phenotype in vitro, in order to obtain optimal cells for adoptive cell transfer therapy. Assessing ex vivo lymph node cultures, dendritic cells, fibroblastic reticular cells, and HP-associated cytokines, we found that stimulation of naïve T cells with anti-CD3/CD28 beads and IL-15 (IL-7 was dispensable) led to the generation of memory-like T cell with a similar phenotype. Both in vitro and in vivo memory-like T cells retained the capacity to efficiently control tumor growth in non-lymphopenic hosts upon adoptive cell transfer. A similar phenotype could be imparted to human peripheral blood leukocytes with comparable culture conditions. Our data reinforce the idea that in vitro-generated memory-like T cells could benefit adoptive cell transfer therapies.
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL), Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Kaiser
authors.forename: Jules
authors.initials: J
authors.lastname: Gadiot
authors.forename: Aurelie
authors.initials: A
authors.lastname: Guislain
authors.forename: Christian U
authors.initials: CU
authors.lastname: Blank
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D008231:Lymphopenia / Q000276:immunology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex