Pre-TCRα supports CD3-dependent reactivation and expansion of TCRα-deficient primary human T-cells
Chimeric antigen receptor technology offers a highly effective means for increasing the anti-tumor effects of autologous adoptive T-cell immunotherapy, and could be made widely available if adapted to the use of allogeneic T-cells. Although gene-editing technology can be used to remove the alloreact...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2014-01-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050116300870 |
| _version_ | 1811228323885350912 |
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| author | Román Galetto Celine Lebuhotel Laurent Poirot Agnès Gouble Maria L Toribio Julianne Smith Andrew Scharenberg |
| author_facet | Román Galetto Celine Lebuhotel Laurent Poirot Agnès Gouble Maria L Toribio Julianne Smith Andrew Scharenberg |
| author_sort | Román Galetto |
| collection | DOAJ |
| description | Chimeric antigen receptor technology offers a highly effective means for increasing the anti-tumor effects of autologous adoptive T-cell immunotherapy, and could be made widely available if adapted to the use of allogeneic T-cells. Although gene-editing technology can be used to remove the alloreactive potential of third party T-cells through destruction of either the α or β T-cell receptor (TCR) subunit genes, this approach results in the associated loss of surface expression of the CD3 complex. This is nonetheless problematic as it results in the lack of an important trophic signal normally mediated by the CD3 complex at the cell surface, potentially compromising T-cell survival in vivo, and eliminating the potential to expand TCR-knockout cells using stimulatory anti-CD3 antibodies. Here, we show that pre-TCRα, a TCRα surrogate that pairs with TCRβ chains to signal proper TCRβ folding during T-cell development, can be expressed in TCRα knockout mature T-cells to support CD3 expression at the cell surface. Cells expressing pre-TCR/CD3 complexes can be activated and expanded using standard CD3/CD28 T-cell activation protocols. Thus, heterologous expression of pre-TCRα represents a promising technology for use in the manufacturing of TCR-deficient T-cells for adoptive immunotherapy applications. |
| first_indexed | 2024-04-12T09:56:06Z |
| format | Article |
| id | doaj.art-1b91df9c50e34331a206e54241e903d4 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-12T09:56:06Z |
| publishDate | 2014-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-1b91df9c50e34331a206e54241e903d42022-12-22T03:37:41ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012014-01-011C10.1038/mtm.2014.21Pre-TCRα supports CD3-dependent reactivation and expansion of TCRα-deficient primary human T-cellsRomán Galetto0Celine Lebuhotel1Laurent Poirot2Agnès Gouble3Maria L Toribio4Julianne Smith5Andrew Scharenberg6Cellectis Therapeutics, Paris, FranceCellectis Therapeutics, Paris, FranceCellectis Therapeutics, Paris, FranceCellectis Therapeutics, Paris, FranceCentro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, SpainCellectis Therapeutics, Paris, FranceCellectis Therapeutics, Paris, FranceChimeric antigen receptor technology offers a highly effective means for increasing the anti-tumor effects of autologous adoptive T-cell immunotherapy, and could be made widely available if adapted to the use of allogeneic T-cells. Although gene-editing technology can be used to remove the alloreactive potential of third party T-cells through destruction of either the α or β T-cell receptor (TCR) subunit genes, this approach results in the associated loss of surface expression of the CD3 complex. This is nonetheless problematic as it results in the lack of an important trophic signal normally mediated by the CD3 complex at the cell surface, potentially compromising T-cell survival in vivo, and eliminating the potential to expand TCR-knockout cells using stimulatory anti-CD3 antibodies. Here, we show that pre-TCRα, a TCRα surrogate that pairs with TCRβ chains to signal proper TCRβ folding during T-cell development, can be expressed in TCRα knockout mature T-cells to support CD3 expression at the cell surface. Cells expressing pre-TCR/CD3 complexes can be activated and expanded using standard CD3/CD28 T-cell activation protocols. Thus, heterologous expression of pre-TCRα represents a promising technology for use in the manufacturing of TCR-deficient T-cells for adoptive immunotherapy applications.http://www.sciencedirect.com/science/article/pii/S2329050116300870 |
| spellingShingle | Román Galetto Celine Lebuhotel Laurent Poirot Agnès Gouble Maria L Toribio Julianne Smith Andrew Scharenberg Pre-TCRα supports CD3-dependent reactivation and expansion of TCRα-deficient primary human T-cells Molecular Therapy: Methods & Clinical Development |
| title | Pre-TCRα supports CD3-dependent reactivation and expansion of TCRα-deficient primary human T-cells |
| title_full | Pre-TCRα supports CD3-dependent reactivation and expansion of TCRα-deficient primary human T-cells |
| title_fullStr | Pre-TCRα supports CD3-dependent reactivation and expansion of TCRα-deficient primary human T-cells |
| title_full_unstemmed | Pre-TCRα supports CD3-dependent reactivation and expansion of TCRα-deficient primary human T-cells |
| title_short | Pre-TCRα supports CD3-dependent reactivation and expansion of TCRα-deficient primary human T-cells |
| title_sort | pre tcrα supports cd3 dependent reactivation and expansion of tcrα deficient primary human t cells |
| url | http://www.sciencedirect.com/science/article/pii/S2329050116300870 |
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