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dc.contributor.authorBaker, Forrest L.
dc.contributor.authorBigley, Austin B.
dc.contributor.authorAgha, Nadia H.
dc.contributor.authorPedlar, Charles R.
dc.contributor.authorO'Connor, Daniel P.
dc.contributor.authorBond, Richard A.
dc.contributor.authorBollard, Catherine M.
dc.contributor.authorKatsanis, Emmanuel
dc.contributor.authorSimpson, Richard J.
dc.date.accessioned2020-03-25T17:38:53Z
dc.date.available2020-03-25T17:38:53Z
dc.date.issued2020-01-24
dc.identifier.citationBaker FL, Bigley AB, Agha NH, Pedlar CR, O'Connor DP, Bond RA, Bollard CM, Katsanis E and Simpson RJ (2020) Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells. Front. Immunol. 10:3082. doi: 10.3389/fimmu.2019.03082en_US
dc.identifier.issn1664-3224
dc.identifier.doi10.3389/fimmu.2019.03082
dc.identifier.urihttp://hdl.handle.net/10150/638062
dc.description.abstractTCR-gamma delta (gamma delta) T-cells are considered important players in the graft-vs.-tumor effect following allogeneic hematopoietic cell transplantation (alloHCT) and have emerged as candidates for adoptive transfer immunotherapy in the treatment of both solid and hematological tumors. Systemic beta-adrenergic receptor (beta-AR) activation has been shown to mobilize TCR-gamma delta T-cells to the blood, potentially serving as an adjuvant for alloHCT and TCR-gamma delta T-cell therapy. We investigated if systemic beta-AR activation, using acute dynamic exercise as an experimental model, can increase the mobilization, ex vivo expansion, and anti-tumor activity of TCR-gamma delta T-cells isolated from the blood of healthy humans. We also sought to investigate the beta-AR subtypes involved, by administering a preferential beta(1)-AR antagonist (bisoprolol) and a non-preferential beta(1) + beta(2)-AR antagonist (nadolol) prior to exercise as part of a randomized placebo controlled cross-over experiment. We found that exercise mobilized TCR-gamma delta cells to blood and augmented their ex vivo expansion by similar to 182% compared to resting blood when stimulated with IL-2 and ZOL for 14-days. Exercise also increased the proportion of CD56+, NKG2D+/CD62L-, CD158a/b/e+ and NKG2A-cells among the expanded TCR-gamma delta cells, and increased their cytotoxic activity against several tumor target cells (K562, U266, 221.AEH) in vitro by 40-60%. Blocking NKG2D on TCR-gamma delta cells in vitro eliminated the augmented cytotoxic effects of exercise against U266 target cells. Furthermore, administering a beta(1) + beta(2)-AR (nadolol), but not a beta(1)-AR (bisoprolol) antagonist prior to exercise abrogated the exercise-induced enhancement in TCR-gamma delta T-cell mobilization and ex vivo expansion. Furthermore, nadolol completely abrogated while bisoprolol partially inhibited the exercise-induced increase in the cytotoxic activity of the expanded TCR-gamma delta T-cells. We conclude that acute systemic beta-AR activation in healthy donors markedly augments the mobilization, ex vivo expansion, and anti-tumor activity of TCR-gamma delta T-cells and that some of these effects are due to beta(2)-AR signaling and phenotypic shifts that promote a dominant activating signal via NKG2D. These findings highlight beta-ARs as potential targets to favorably alter the composition of allogeneic peripheral blood stem cell grafts and improve the potency of TCR-gamma delta T-cell immune cell therapeutics.en_US
dc.language.isoenen_US
dc.publisherFRONTIERS MEDIA SAen_US
dc.rightsCopyright © 2020 Baker, Bigley, Agha, Pedlar, O'Connor, Bond, Bollard, Katsanis and Simpson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subjectexercise immunologyen_US
dc.subjectbeta-blockersen_US
dc.subjectgamma-delta t-cellsen_US
dc.subjectexerciseen_US
dc.titleSystemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cellsen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Dept Immunobiolen_US
dc.contributor.departmentUniv Arizona, Dept Pediaten_US
dc.contributor.departmentUniv Arizona, Dept Nutr Scien_US
dc.identifier.journalFRONTIERS IN IMMUNOLOGYen_US
dc.description.noteOpen access journalen_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.pii10.3389/fimmu.2019.03082
dc.source.journaltitleFrontiers in Immunology
dc.source.volume10
refterms.dateFOA2020-03-25T17:38:54Z


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Copyright © 2020 Baker, Bigley, Agha, Pedlar, O'Connor, Bond, Bollard, Katsanis and Simpson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Except where otherwise noted, this item's license is described as Copyright © 2020 Baker, Bigley, Agha, Pedlar, O'Connor, Bond, Bollard, Katsanis and Simpson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.