Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques
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Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques. / Berger, Carolina; Berger, Michael; Beard, Brian C; Kiem, Hans-Peter; Gooley, Theodore A; Riddell, Stanley R.
In: PLOS ONE, Vol. 8, No. 2, 2013, p. e56268.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques
AU - Berger, Carolina
AU - Berger, Michael
AU - Beard, Brian C
AU - Kiem, Hans-Peter
AU - Gooley, Theodore A
AU - Riddell, Stanley R
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Adoptive Transfer
KW - Animals
KW - Apoptosis/drug effects
KW - Bone Marrow/drug effects
KW - CD8-Positive T-Lymphocytes/cytology
KW - Cell Movement/drug effects
KW - Cell Proliferation/drug effects
KW - Clone Cells/cytology
KW - Cytomegalovirus/immunology
KW - Immunologic Memory/immunology
KW - Interleukin-15/administration & dosage
KW - Lymph Nodes/drug effects
KW - Macaca nemestrina
KW - Time Factors
U2 - 10.1371/journal.pone.0056268
DO - 10.1371/journal.pone.0056268
M3 - SCORING: Journal article
C2 - 23418547
VL - 8
SP - e56268
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 2
ER -