Proliferation-Linked Apoptosis of Adoptively Transferred T Cells after IL-15 Administration in Macaques |
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Authors: | Carolina Berger Michael Berger Brian C. Beard Hans-Peter Kiem Theodore A. Gooley Stanley R. Riddell |
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Affiliation: | 1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.; 2. Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.; 3. Focus Group “Clinical Cell Processing and Purification”, Institute for Advanced Study, Technical University of Munich, Munich, Germany.; Saint Louis University School of Medicine, United States of America, |
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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 (TCM/E) cells is enhanced in vivo by administering IL-15. TCM/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+ TCM/E cells in lymphoreplete hosts. |
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