Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques.
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 challen...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3572023?pdf=render |
| _version_ | 1818864356616568832 |
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| author | Carolina Berger Michael Berger Brian C Beard Hans-Peter Kiem Theodore A Gooley Stanley R Riddell |
| author_facet | Carolina Berger Michael Berger Brian C Beard Hans-Peter Kiem Theodore A Gooley Stanley R Riddell |
| author_sort | Carolina Berger |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T10:30:21Z |
| format | Article |
| id | doaj.art-53f43b84593f4f80abd90c37a3119236 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T10:30:21Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-53f43b84593f4f80abd90c37a31192362022-12-21T20:25:46ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0182e5626810.1371/journal.pone.0056268Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques.Carolina BergerMichael BergerBrian C BeardHans-Peter KiemTheodore A GooleyStanley R RiddellThe 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.http://europepmc.org/articles/PMC3572023?pdf=render |
| spellingShingle | Carolina Berger Michael Berger Brian C Beard Hans-Peter Kiem Theodore A Gooley Stanley R Riddell Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques. PLoS ONE |
| title | Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques. |
| title_full | Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques. |
| title_fullStr | Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques. |
| title_full_unstemmed | Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques. |
| title_short | Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques. |
| title_sort | proliferation linked apoptosis of adoptively transferred t cells after il 15 administration in macaques |
| url | http://europepmc.org/articles/PMC3572023?pdf=render |
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