Spatiotemporal in vivo tracking of polyclonal human regulatory T cells reveals a role for innate immune cells in Treg transplant recruitment

Article


Jacob, J., Nadkarni, S., Volpe, A., Peng, Q., Tung, S. L., Hannen, R. F., Mohseni, Y. R., Scotta, C., Marelli-Berg, F. M., Lechler, R. I., Smyth, L., Fruhwirth, G. O. and Lombardi, G. 2020. Spatiotemporal in vivo tracking of polyclonal human regulatory T cells reveals a role for innate immune cells in Treg transplant recruitment. Molecular Therapy - Methods and Clinical Development. https://doi.org/10.1016/j.omtm.2020.12.003
AuthorsJacob, J., Nadkarni, S., Volpe, A., Peng, Q., Tung, S. L., Hannen, R. F., Mohseni, Y. R., Scotta, C., Marelli-Berg, F. M., Lechler, R. I., Smyth, L., Fruhwirth, G. O. and Lombardi, G.
Abstract

Regulatory T cells (Tregs) are emerging as a new cell-based therapy in solid organ transplantation. Adoptive transfer of Tregs was shown preclinically to protect from graft rejection, and the safety of Treg therapy has been demonstrated in clinical trials. Despite these successes, the in vivo distribution and persistence of adoptively transferred Tregs remained elusive which hampers clinical translation. Here, we isolated human Tregs using a GMP-compatible protocol and lentivirally transduced them with the human sodium iodide symporter to render them traceable in vivo by radionuclide imaging. Engineered human Tregs were characterized for phenotype, survival, suppressive capacity, and reporter function. To study their trafficking behaviour, they were subsequently administered to humanized mice with human skin transplants. Traceable Tregs were quantified in skin grafts by non-invasive nanoSPECT/CT for up to 40 days and results validated ex vivo. Using this approach, we demonstrated that Treg trafficking to skin grafts was regulated by the presence of recipient Gr-1⁺ innate immune cells. We demonstrated the utility of radionuclide reporter gene afforded quantitative Treg in vivo tracking thereby addressing a fundamental need in Treg therapy development and offering clinically compatible methodology for future Treg therapy imaging in humans.

JournalMolecular Therapy - Methods and Clinical Development
ISSN2329-0501
Year2020
PublisherElsevier (Cell Press)
Accepted author manuscript
License
File Access Level
Anyone
Digital Object Identifier (DOI)https://doi.org/10.1016/j.omtm.2020.12.003
Publication dates
Online10 Dec 2020
Publication process dates
Accepted02 Dec 2020
Deposited15 Dec 2020
FunderBritish Heart Foundation
Medical Research Council
Cancer Research UK
Wellcome Trust
Engineering and Physical Sciences Research Council
National Institute for Health Research
Copyright holder© 2021 The Authors
Permalink -

https://repository.uel.ac.uk/item/88w79

Download files

Accepted author manuscript
1-s2.0-S2329050120302515-main.pdf
License: CC BY 4.0
File access level: Anyone

  • 14
    total views
  • 5
    total downloads
  • 10
    views this month
  • 3
    downloads this month

Export as

Related outputs

B lymphocytes contribute to indirect pathway T cell sensitisation via acquisition of extracellular vesicles
Becker, P. D., Ratnasothy, K., Sen, M., Peng, Q., Romano, M., Bazoer, J., Suvitra, E., Stout, A., Hylton, S. G., Dorling, A., Lechler, R. I., Smyth, L. and Lombardi, G. 2020. B lymphocytes contribute to indirect pathway T cell sensitisation via acquisition of extracellular vesicles. American Journal of Transplantation. https://doi.org/10.1111/ajt.16088
Regulatory T Cell Extracellular Vesicles Modify T-Effector Cell Cytokine Production and Protect Against Human Skin Allograft Damage
Tung, S. L., Fanelli, G., Matthews, R. I., Bazoer, J., Letizia, M., Vizcay-Barrena, G., Faruqu, F. N., Philippeos, C., Hannen, R., Al-Jamal, K. T., Smyth, L. and Lombardi, G. 2020. Regulatory T Cell Extracellular Vesicles Modify T-Effector Cell Cytokine Production and Protect Against Human Skin Allograft Damage. Frontiers in Cell and Developmental Biology. 8 (Art. 317). https://doi.org/10.3389/fcell.2020.00317
Application of carbon nanotubes in cancer vaccines: Achievements, challenges and chances
Hassan, Hatem A.F.M., Diebold, Sandra S., Smyth, L., Walters, Adam A., Lombardi, Giovanna and Al-Jamal, Khuloud T. 2019. Application of carbon nanotubes in cancer vaccines: Achievements, challenges and chances. Journal of Controlled Release. 297, pp. 79-90. https://doi.org/10.1016/j.jconrel.2019.01.017
Protease Activated Receptor 4 as a Novel Modulator of Regulatory T Cell Function
Peng, Q., Ratnasothy, K., Boardman, D. A., Jacob, J., Tung, S. T., McCluskey, D., Smyth, L., Lechler, R. I., Dorling, A. and Lombardi, G. 2019. Protease Activated Receptor 4 as a Novel Modulator of Regulatory T Cell Function. Frontiers in Immunology. 10 (Art. 1311). https://doi.org/10.3389/fimmu.2019.01311
Membrane radiolabelling of exosomes for comparative biodistribution analysis in immunocompetent and immunodeficient mice – a novel and universal approach
Faruqu, Farid N., Wang, Julie Tzu-Wen, Xu, Lizhou, McNickle, Luke, Chong, Eden Ming-Yiu, Walters, Adam, Gurney, Mark, Clayton, Aled, Smyth, L., Hider, Robert, Sosabowski, Jane and Al-Jamal, Khuloud T. 2019. Membrane radiolabelling of exosomes for comparative biodistribution analysis in immunocompetent and immunodeficient mice – a novel and universal approach. Theranostics. 9 (6), pp. 1666-1682. https://doi.org/10.7150/thno.27891
Nox2 in regulatory T cells promotes angiotensin II–induced cardiovascular remodeling
Emmerson, Amber, Trevelin, Silvia Cellone, Mongue-Din, Heloise, Becker, Pablo D., Ortiz, Carla, Smyth, L., Peng, Qi, Elgueta, Raul, Sawyer, Greta, Ivetic, Aleksandar, Lechler, Robert I., Lombardi, Giovanna and Shah, Ajay M. 2018. Nox2 in regulatory T cells promotes angiotensin II–induced cardiovascular remodeling. Journal of Clinical Investigation. 128 (7), pp. 3088-3101. https://doi.org/10.1172/JCI97490
Regulatory T cell-derived extracellular vesicles modify dendritic cell function
Tung, Sim L., Boardman, Dominic A., Sen, Monica, Letizia, Marilena, Peng, Qi, Cianci, Nicole, Dioni, Laura, Carlin, Leo M., Lechler, Robert, Bollati, Valentina, Lombardi, Giovanna and Smyth, L. 2018. Regulatory T cell-derived extracellular vesicles modify dendritic cell function. Scientific Reports. 8, p. 6065. https://doi.org/10.1038/s41598-018-24531-8
Galectin-1 is required for the regulatory function of B cells
Alhabbab, R., Blair, P., Smyth, L., Ratnasothy, K., Peng, Q., Moreau, A., Lechler, R., Elgueta, R. and Lombardi, G. 2018. Galectin-1 is required for the regulatory function of B cells. Scientific Reports. 8 (2725). https://doi.org/10.1038/s41598-018-19965-z
Constitutive expression of the anti-apoptotic Bcl-2 family member A1 in murine endothelial cells leads to transplant tolerance
Smyth, L., Meader, Lucy, Xiao, Fang, Woodward, Martin, Brady, Hugh J., Lechler, Robert and Lombardi, Giovanna 2017. Constitutive expression of the anti-apoptotic Bcl-2 family member A1 in murine endothelial cells leads to transplant tolerance. Clinical and Experimental Immunology. 188 (2), pp. 219-225. https://doi.org/10.1111/cei.12931
Dual stimulation of antigen presenting cells using carbon nanotube-based vaccine delivery system for cancer immunotherapy
Hassan, Hatem A.F.M., Smyth, L., Wang, Julie T.-W., Costa, Pedro M., Ratnasothy, Kulachelvy, Diebold, Sandra S., Lombardi, Giovanna and Al-Jamal, Khuloud T. 2016. Dual stimulation of antigen presenting cells using carbon nanotube-based vaccine delivery system for cancer immunotherapy. Biomaterials. 104, pp. 310-322. https://doi.org/10.1016/j.biomaterials.2016.07.005
Regulatory T Cell-Derived Exosomes: Possible Therapeutic and Diagnostic Tools in Transplantation
Agarwal, Akansha, Fanelli, Giorgia, Letizia, Marilena, Tung, Sim Lai, Boardman, Dominic, Lechler, Robert, Lombardi, Giovanna and Smyth, L. 2014. Regulatory T Cell-Derived Exosomes: Possible Therapeutic and Diagnostic Tools in Transplantation. Frontiers in Immunology. 5.
UK–Russia Researcher Links Workshop: extracellular vesicles – mechanisms of biogenesis and roles in disease pathogenesis, M.V. Lomonosov Moscow State University, Moscow, Russia, 1–5 March 2015
Kapustin, Alexander N., Kalinina, Natalia, Lopatina, Tatiana, Davidson, Sean M., Iraci, Nunzio, Tamkovich, Svetlana, Smyth, L., Ter-Ovanesyan, Dmitry, Evtushenko, Evgeniy G., Savelieva, Olga, Bertazzo, Sergio, Aushev, Vassiliy, Dragovic, Rebecca, Gracia, Tannia, Heck, Margarete, Parfyonova, Yelena V., Shanahan, Catherine M. and Tkachuk, Vsevolod 2015. UK–Russia Researcher Links Workshop: extracellular vesicles – mechanisms of biogenesis and roles in disease pathogenesis, M.V. Lomonosov Moscow State University, Moscow, Russia, 1–5 March 2015. Journal of Extracellular Vesicles. 4 (1), p. 28094. https://doi.org/10.3402/jev.v4.28094
Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model
Alhabbab, R., Blair, P., Elgueta, R., Stolarczyk, E., Marks, E., Becker, P. D., Ratnasothy, K., Smyth, L., Safinia, N., Sharif-Paghaleh, E., O’Connell, S., Noelle, R. J., Lord, G. M., Howard, J. K., Spencer, J., Lechler, R. I. and Lombardi, G. 2015. Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model. Scientific Reports. 5, p. 11554.
Carbon nanotubes' surface chemistry determines their potency as vaccine nanocarriers in vitro and in vivo
Hassan, Hatem A.F.M., Smyth, L., Rubio, Noelia, Ratnasothy, Kulachelvy, Wang, Julie T.-W., Bansal, Sukhvinder S., Summers, Huw D., Diebold, Sandra S., Lombardi, Giovanna and Al-Jamal, Khuloud T. 2016. Carbon nanotubes' surface chemistry determines their potency as vaccine nanocarriers in vitro and in vivo. Journal of Controlled Release. 225, pp. 205-216. https://doi.org/10.1016/j.jconrel.2016.01.030
Continuous acquisition of MHC:peptide complexes by recipient cells contributes to the generation of anti-graft CD8+T cell immunity
Smyth, L., Lechler, Robert I and Lombardi, Giovanna 2016. Continuous acquisition of MHC:peptide complexes by recipient cells contributes to the generation of anti-graft CD8+T cell immunity. American Journal of Transplantation. 17 (1), pp. 60-68. https://doi.org/10.1111/ajt.13996
What Is Direct Allorecognition?
Boardman, Dominic A., Jacob, Jacinta, Smyth, L., Lombardi, Giovanna and Lechler, Robert I. 2016. What Is Direct Allorecognition? Current Transplantation Reports. 3 (4), pp. 275-283. https://doi.org/10.1007/s40472-016-0115-8
Treg therapy in transplantation a general overview
Romano, Marco, Tung, Sim Lai, Smyth, L. and Lombardi, Giovanna 2016. Treg therapy in transplantation a general overview. Transplant International. 30 (8), pp. 745-753. https://doi.org/10.1111/tri.12909
Expression of a chimeric antigen receptor specific for donor HLA class I enhances the potency of human regulatory T cells in preventing human skin transplant rejection
Boardman, Dominic A., Philippeos, Christina, Fruhwirth, Gilbert O., Ibrahim, Mohammad A. A., Hannen, Rosalind F., Cooper, Dianne, Marelli-Berg, Federica M., Watt, Fiona M., Lechler, Robert I., Maher, John, Smyth, L. and Lombardi, Giovanna 2016. Expression of a chimeric antigen receptor specific for donor HLA class I enhances the potency of human regulatory T cells in preventing human skin transplant rejection. American Journal of Transplantation. 17 (4), pp. 931-943. https://doi.org/10.1111/ajt.14185