title: Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques.
abstract: The adoptive transfer of antigen-specific effector T cells is being used to treat human infections and malignancy. T cell persistence is a prerequisite for therapeutic efficacy, but reliably establishing a high-level and durable T cell response by transferring cultured CD8(+) T cells remains challenging. Thus, strategies that promote a transferred high-level T cell response may improve the efficacy of T cell therapy. Lymphodepletion enhances persistence of transferred T cells in mice in part by reducing competition for IL-15, a common γ-chain cytokine that promotes T cell memory, but lymphodepleting regimens have toxicity. IL-15 can be safely administered and has minimal effects on CD4(+) regulatory T cells at low doses, making it an attractive adjunct in adoptive T cell therapy. Here, we show in lymphoreplete macaca nemestrina, that proliferation of adoptively transferred central memory-derived CD8(+) effector T (T(CM/E)) cells is enhanced in vivo by administering IL-15. T(CM/E) cells migrated to memory niches, persisted, and acquired both central memory and effector memory phenotypes regardless of the cytokine treatment. Unexpectedly, despite maintaining T cell proliferation, IL-15 did not augment the magnitude of the transferred T cell response in blood, bone marrow, or lymph nodes. T cells induced to proliferate by IL-15 displayed increased apoptosis demonstrating that enhanced cycling was balanced by cell death. These results suggest that homeostatic mechanisms that regulate T cell numbers may interfere with strategies to augment a high-level T cell response by adoptive transfer of CD8(+) T(CM/E) cells in lymphoreplete hosts.
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. cberger@fhcrc.org
authors: Carolina
authors: C
authors: Berger
authors: Michael
authors: M
authors: Berger
authors: Brian C
authors: BC
authors: Beard
authors: Hans-Peter
authors: HP
authors: Kiem
authors: Theodore A
authors: TA
authors: Gooley
authors: Stanley R
authors: SR
authors: Riddell
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects*; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D003587:Cytomegalovirus / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D019409:Interleukin-15 / Q000008:administration & dosage* / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008254:Macaca nemestrina; D013997:Time Factors
chemical_list: D019409:Interleukin-15