title: CD8 T cell priming in the presence of IFN-α renders CTLs with improved responsiveness to homeostatic cytokines and recall antigens: important traits for adoptive T cell therapy.
abstract: Previous mouse and human studies have demonstrated that direct IFN-α/β signaling on naive CD8 T cells is critical to support their expansion and acquisition of effector functions. In this study, we show that human naive CD8 T cells primed in the presence of IFN-α possess a heightened ability to respond to homeostatic cytokines and to secondary Ag stimulation, but rather than differentiating to effector or memory CTLs, they preserve nature-like phenotypic features. These are qualities associated with greater efficacy in adoptive immunotherapy. In a mouse model of adoptive transfer, CD8 T cells primed in the presence of IFN-α are able to persist and to mediate a robust recall response even after a long period of naturally driven homeostatic maintenance. The long-lasting persistence of IFN-α-primed CD8 T cells is favored by their enhanced responsiveness to IL-15 and IL-7, as demonstrated in IL-15(-/-) and IL-7(-/-) recipient mice. In humans, exposure to IFN-α during in vitro priming of naive HLA-A2(+) CD8 T cells with autologous dendritic cells loaded with MART1(26-35) peptide renders CD8 T cells with an improved capacity to respond to homeostatic cytokines and to specifically lyse MART1-expressing melanoma cells. Furthermore, in a mouse model of melanoma, adoptive transfer of tumor-specific CD8 T cells primed ex vivo in the presence of IFN-α exhibits an improved ability to contain tumor progression. Therefore, exposure to IFN-α during priming of naive CD8 T cells imprints decisive information on the expanded cells that can be exploited to improve the efficacy of adoptive T cell therapy.
authors.affiliation: Division of Gene Therapy and Hepatology, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain. mshervas@unav.es
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervas-Stubbs
authors.forename: Uxua
authors.initials: U
authors.lastname: Mancheño
authors.forename: Jose-Ignacio
authors.initials: JI
authors.lastname: Riezu-Boj
authors.forename: Ana
authors.initials: A
authors.lastname: Larraga
authors.forename: Maria C
authors.initials: MC
authors.lastname: Ochoa
authors.forename: Diego
authors.initials: D
authors.lastname: Alignani
authors.forename: Carlos
authors.initials: C
authors.lastname: Alfaro
authors.forename: Aizea
authors.initials: A
authors.lastname: Morales-Kastresana
authors.forename: Iranzu
authors.initials: I
authors.lastname: Gonzalez
authors.forename: Esther
authors.initials: E
authors.lastname: Larrea
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Pircher
authors.forename: Agnes
authors.initials: A
authors.lastname: Le Bon
authors.forename: Jose M
authors.initials: JM
authors.lastname: Lopez-Picazo
authors.forename: Salvador
authors.initials: S
authors.lastname: Martín-Algarra
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000941:Antigens / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D006706:Homeostasis / Q000276:immunology*; D006801:Humans; D007117:Immunization, Secondary / Q000379:methods*; D007156:Immunologic Memory; D016898:Interferon-alpha / Q000502:physiology*; D019409:Interleukin-15 / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
chemical_list: D000941:Antigens; D016207:Cytokines; D016898:Interferon-alpha; D019409:Interleukin-15; D020381:Interleukin-17