Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors
Abstract Understanding cellular decisions due to receptor–ligand interactions at cell–cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Patel, Ashna [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2023 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2023 |
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| Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 43(2023), 1 vom: 18. Dez., Seite 132-150 |
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| Übergeordnetes Werk: |
volume:43 ; year:2023 ; number:1 ; day:18 ; month:12 ; pages:132-150 |
| Links: |
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| DOI / URN: |
10.1038/s44318-023-00012-1 |
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| Katalog-ID: |
SPR054273978 |
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| 100 | 1 | |a Patel, Ashna |e verfasserin |0 (orcid)0009-0008-4502-3990 |4 aut | |
| 245 | 1 | 0 | |a Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors |
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| 520 | |a Abstract Understanding cellular decisions due to receptor–ligand interactions at cell–cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands—called CombiCells—to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor–ligand interactions at cell–cell interfaces. | ||
| 520 | |a Synopsis The inherent difficulty in manipulating cell surface proteins limits our ability to study cell–cell recognition. This work develops a platform for the combinatorial display of cell surface ligands (CombiCells), and demonstrates its value for determining the sensitivity and costimulatory requirements for T cells recognizing antigens on target cells. Proteins fused to SpyTag can be covalently coupled to the surfaces of cells expressing a membrane-anchored form of SpyCatcher.This enables rapid production of cells expressing different concentrations and combinations of multiple proteins, including antigens and accessory receptor ligands.Using CombiCells, the T cell receptor is found to be 10-fold more sensitive to its target ligand pMHC than CARs and BiTEs are to their target, CD19.By presenting T cells with Spytag-pMHC, PD-1 engagement is shown to promiscuously inhibit T cell activation in the presence or absence of CD2 or CD28 co-stimulation. | ||
| 520 | |a Expression of SpyCatcher on the cell surface allows tritration and combinatorial display of purified ligands fused to Spytag, enabling controlled investigation of receptor–ligand interactions at immune cell interfaces. | ||
| 650 | 4 | |a Receptor/Ligand Interactions |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Cell–Cell Recognition |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Surface Ligand Presentation |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a T Cell Antigen Sensitivity |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Chimeric Antigen Receptors |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Andre, Violaine |4 aut | |
| 700 | 1 | |a Eguiguren, Sofia Bustamante |4 aut | |
| 700 | 1 | |a Barton, Michael I |0 (orcid)0000-0002-9263-6481 |4 aut | |
| 700 | 1 | |a Burton, Jake |4 aut | |
| 700 | 1 | |a Denham, Eleanor M |4 aut | |
| 700 | 1 | |a Pettmann, Johannes |4 aut | |
| 700 | 1 | |a Mørch, Alexander M |0 (orcid)0000-0002-1881-2424 |4 aut | |
| 700 | 1 | |a Kutuzov, Mikhail A |0 (orcid)0000-0003-3386-4350 |4 aut | |
| 700 | 1 | |a Siller-Farfán, Jesús A |4 aut | |
| 700 | 1 | |a Dustin, Michael L |0 (orcid)0000-0003-4983-6389 |4 aut | |
| 700 | 1 | |a van der Merwe, P Anton |0 (orcid)0000-0001-9902-6590 |4 aut | |
| 700 | 1 | |a Dushek, Omer |0 (orcid)0000-0001-5847-5226 |4 aut | |
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10.1038/s44318-023-00012-1 doi (DE-627)SPR054273978 (SPR)s44318-023-00012-1-e DE-627 ger DE-627 rakwb eng Patel, Ashna verfasserin (orcid)0009-0008-4502-3990 aut Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Understanding cellular decisions due to receptor–ligand interactions at cell–cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands—called CombiCells—to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor–ligand interactions at cell–cell interfaces. Synopsis The inherent difficulty in manipulating cell surface proteins limits our ability to study cell–cell recognition. This work develops a platform for the combinatorial display of cell surface ligands (CombiCells), and demonstrates its value for determining the sensitivity and costimulatory requirements for T cells recognizing antigens on target cells. Proteins fused to SpyTag can be covalently coupled to the surfaces of cells expressing a membrane-anchored form of SpyCatcher.This enables rapid production of cells expressing different concentrations and combinations of multiple proteins, including antigens and accessory receptor ligands.Using CombiCells, the T cell receptor is found to be 10-fold more sensitive to its target ligand pMHC than CARs and BiTEs are to their target, CD19.By presenting T cells with Spytag-pMHC, PD-1 engagement is shown to promiscuously inhibit T cell activation in the presence or absence of CD2 or CD28 co-stimulation. Expression of SpyCatcher on the cell surface allows tritration and combinatorial display of purified ligands fused to Spytag, enabling controlled investigation of receptor–ligand interactions at immune cell interfaces. Receptor/Ligand Interactions (dpeaa)DE-He213 Cell–Cell Recognition (dpeaa)DE-He213 Surface Ligand Presentation (dpeaa)DE-He213 T Cell Antigen Sensitivity (dpeaa)DE-He213 Chimeric Antigen Receptors (dpeaa)DE-He213 Andre, Violaine aut Eguiguren, Sofia Bustamante aut Barton, Michael I (orcid)0000-0002-9263-6481 aut Burton, Jake aut Denham, Eleanor M aut Pettmann, Johannes aut Mørch, Alexander M (orcid)0000-0002-1881-2424 aut Kutuzov, Mikhail A (orcid)0000-0003-3386-4350 aut Siller-Farfán, Jesús A aut Dustin, Michael L (orcid)0000-0003-4983-6389 aut van der Merwe, P Anton (orcid)0000-0001-9902-6590 aut Dushek, Omer (orcid)0000-0001-5847-5226 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2023), 1 vom: 18. Dez., Seite 132-150 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2023 number:1 day:18 month:12 pages:132-150 https://dx.doi.org/10.1038/s44318-023-00012-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 43 2023 1 18 12 132-150 |
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10.1038/s44318-023-00012-1 doi (DE-627)SPR054273978 (SPR)s44318-023-00012-1-e DE-627 ger DE-627 rakwb eng Patel, Ashna verfasserin (orcid)0009-0008-4502-3990 aut Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Understanding cellular decisions due to receptor–ligand interactions at cell–cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands—called CombiCells—to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor–ligand interactions at cell–cell interfaces. Synopsis The inherent difficulty in manipulating cell surface proteins limits our ability to study cell–cell recognition. This work develops a platform for the combinatorial display of cell surface ligands (CombiCells), and demonstrates its value for determining the sensitivity and costimulatory requirements for T cells recognizing antigens on target cells. Proteins fused to SpyTag can be covalently coupled to the surfaces of cells expressing a membrane-anchored form of SpyCatcher.This enables rapid production of cells expressing different concentrations and combinations of multiple proteins, including antigens and accessory receptor ligands.Using CombiCells, the T cell receptor is found to be 10-fold more sensitive to its target ligand pMHC than CARs and BiTEs are to their target, CD19.By presenting T cells with Spytag-pMHC, PD-1 engagement is shown to promiscuously inhibit T cell activation in the presence or absence of CD2 or CD28 co-stimulation. Expression of SpyCatcher on the cell surface allows tritration and combinatorial display of purified ligands fused to Spytag, enabling controlled investigation of receptor–ligand interactions at immune cell interfaces. Receptor/Ligand Interactions (dpeaa)DE-He213 Cell–Cell Recognition (dpeaa)DE-He213 Surface Ligand Presentation (dpeaa)DE-He213 T Cell Antigen Sensitivity (dpeaa)DE-He213 Chimeric Antigen Receptors (dpeaa)DE-He213 Andre, Violaine aut Eguiguren, Sofia Bustamante aut Barton, Michael I (orcid)0000-0002-9263-6481 aut Burton, Jake aut Denham, Eleanor M aut Pettmann, Johannes aut Mørch, Alexander M (orcid)0000-0002-1881-2424 aut Kutuzov, Mikhail A (orcid)0000-0003-3386-4350 aut Siller-Farfán, Jesús A aut Dustin, Michael L (orcid)0000-0003-4983-6389 aut van der Merwe, P Anton (orcid)0000-0001-9902-6590 aut Dushek, Omer (orcid)0000-0001-5847-5226 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2023), 1 vom: 18. Dez., Seite 132-150 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2023 number:1 day:18 month:12 pages:132-150 https://dx.doi.org/10.1038/s44318-023-00012-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 43 2023 1 18 12 132-150 |
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10.1038/s44318-023-00012-1 doi (DE-627)SPR054273978 (SPR)s44318-023-00012-1-e DE-627 ger DE-627 rakwb eng Patel, Ashna verfasserin (orcid)0009-0008-4502-3990 aut Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Understanding cellular decisions due to receptor–ligand interactions at cell–cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands—called CombiCells—to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor–ligand interactions at cell–cell interfaces. Synopsis The inherent difficulty in manipulating cell surface proteins limits our ability to study cell–cell recognition. This work develops a platform for the combinatorial display of cell surface ligands (CombiCells), and demonstrates its value for determining the sensitivity and costimulatory requirements for T cells recognizing antigens on target cells. Proteins fused to SpyTag can be covalently coupled to the surfaces of cells expressing a membrane-anchored form of SpyCatcher.This enables rapid production of cells expressing different concentrations and combinations of multiple proteins, including antigens and accessory receptor ligands.Using CombiCells, the T cell receptor is found to be 10-fold more sensitive to its target ligand pMHC than CARs and BiTEs are to their target, CD19.By presenting T cells with Spytag-pMHC, PD-1 engagement is shown to promiscuously inhibit T cell activation in the presence or absence of CD2 or CD28 co-stimulation. Expression of SpyCatcher on the cell surface allows tritration and combinatorial display of purified ligands fused to Spytag, enabling controlled investigation of receptor–ligand interactions at immune cell interfaces. Receptor/Ligand Interactions (dpeaa)DE-He213 Cell–Cell Recognition (dpeaa)DE-He213 Surface Ligand Presentation (dpeaa)DE-He213 T Cell Antigen Sensitivity (dpeaa)DE-He213 Chimeric Antigen Receptors (dpeaa)DE-He213 Andre, Violaine aut Eguiguren, Sofia Bustamante aut Barton, Michael I (orcid)0000-0002-9263-6481 aut Burton, Jake aut Denham, Eleanor M aut Pettmann, Johannes aut Mørch, Alexander M (orcid)0000-0002-1881-2424 aut Kutuzov, Mikhail A (orcid)0000-0003-3386-4350 aut Siller-Farfán, Jesús A aut Dustin, Michael L (orcid)0000-0003-4983-6389 aut van der Merwe, P Anton (orcid)0000-0001-9902-6590 aut Dushek, Omer (orcid)0000-0001-5847-5226 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2023), 1 vom: 18. Dez., Seite 132-150 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2023 number:1 day:18 month:12 pages:132-150 https://dx.doi.org/10.1038/s44318-023-00012-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 43 2023 1 18 12 132-150 |
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10.1038/s44318-023-00012-1 doi (DE-627)SPR054273978 (SPR)s44318-023-00012-1-e DE-627 ger DE-627 rakwb eng Patel, Ashna verfasserin (orcid)0009-0008-4502-3990 aut Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Understanding cellular decisions due to receptor–ligand interactions at cell–cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands—called CombiCells—to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor–ligand interactions at cell–cell interfaces. Synopsis The inherent difficulty in manipulating cell surface proteins limits our ability to study cell–cell recognition. This work develops a platform for the combinatorial display of cell surface ligands (CombiCells), and demonstrates its value for determining the sensitivity and costimulatory requirements for T cells recognizing antigens on target cells. Proteins fused to SpyTag can be covalently coupled to the surfaces of cells expressing a membrane-anchored form of SpyCatcher.This enables rapid production of cells expressing different concentrations and combinations of multiple proteins, including antigens and accessory receptor ligands.Using CombiCells, the T cell receptor is found to be 10-fold more sensitive to its target ligand pMHC than CARs and BiTEs are to their target, CD19.By presenting T cells with Spytag-pMHC, PD-1 engagement is shown to promiscuously inhibit T cell activation in the presence or absence of CD2 or CD28 co-stimulation. Expression of SpyCatcher on the cell surface allows tritration and combinatorial display of purified ligands fused to Spytag, enabling controlled investigation of receptor–ligand interactions at immune cell interfaces. Receptor/Ligand Interactions (dpeaa)DE-He213 Cell–Cell Recognition (dpeaa)DE-He213 Surface Ligand Presentation (dpeaa)DE-He213 T Cell Antigen Sensitivity (dpeaa)DE-He213 Chimeric Antigen Receptors (dpeaa)DE-He213 Andre, Violaine aut Eguiguren, Sofia Bustamante aut Barton, Michael I (orcid)0000-0002-9263-6481 aut Burton, Jake aut Denham, Eleanor M aut Pettmann, Johannes aut Mørch, Alexander M (orcid)0000-0002-1881-2424 aut Kutuzov, Mikhail A (orcid)0000-0003-3386-4350 aut Siller-Farfán, Jesús A aut Dustin, Michael L (orcid)0000-0003-4983-6389 aut van der Merwe, P Anton (orcid)0000-0001-9902-6590 aut Dushek, Omer (orcid)0000-0001-5847-5226 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2023), 1 vom: 18. Dez., Seite 132-150 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2023 number:1 day:18 month:12 pages:132-150 https://dx.doi.org/10.1038/s44318-023-00012-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 43 2023 1 18 12 132-150 |
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10.1038/s44318-023-00012-1 doi (DE-627)SPR054273978 (SPR)s44318-023-00012-1-e DE-627 ger DE-627 rakwb eng Patel, Ashna verfasserin (orcid)0009-0008-4502-3990 aut Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Understanding cellular decisions due to receptor–ligand interactions at cell–cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands—called CombiCells—to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor–ligand interactions at cell–cell interfaces. Synopsis The inherent difficulty in manipulating cell surface proteins limits our ability to study cell–cell recognition. This work develops a platform for the combinatorial display of cell surface ligands (CombiCells), and demonstrates its value for determining the sensitivity and costimulatory requirements for T cells recognizing antigens on target cells. Proteins fused to SpyTag can be covalently coupled to the surfaces of cells expressing a membrane-anchored form of SpyCatcher.This enables rapid production of cells expressing different concentrations and combinations of multiple proteins, including antigens and accessory receptor ligands.Using CombiCells, the T cell receptor is found to be 10-fold more sensitive to its target ligand pMHC than CARs and BiTEs are to their target, CD19.By presenting T cells with Spytag-pMHC, PD-1 engagement is shown to promiscuously inhibit T cell activation in the presence or absence of CD2 or CD28 co-stimulation. Expression of SpyCatcher on the cell surface allows tritration and combinatorial display of purified ligands fused to Spytag, enabling controlled investigation of receptor–ligand interactions at immune cell interfaces. Receptor/Ligand Interactions (dpeaa)DE-He213 Cell–Cell Recognition (dpeaa)DE-He213 Surface Ligand Presentation (dpeaa)DE-He213 T Cell Antigen Sensitivity (dpeaa)DE-He213 Chimeric Antigen Receptors (dpeaa)DE-He213 Andre, Violaine aut Eguiguren, Sofia Bustamante aut Barton, Michael I (orcid)0000-0002-9263-6481 aut Burton, Jake aut Denham, Eleanor M aut Pettmann, Johannes aut Mørch, Alexander M (orcid)0000-0002-1881-2424 aut Kutuzov, Mikhail A (orcid)0000-0003-3386-4350 aut Siller-Farfán, Jesús A aut Dustin, Michael L (orcid)0000-0003-4983-6389 aut van der Merwe, P Anton (orcid)0000-0001-9902-6590 aut Dushek, Omer (orcid)0000-0001-5847-5226 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2023), 1 vom: 18. Dez., Seite 132-150 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2023 number:1 day:18 month:12 pages:132-150 https://dx.doi.org/10.1038/s44318-023-00012-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 43 2023 1 18 12 132-150 |
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Enthalten in The EMBO Journal 43(2023), 1 vom: 18. Dez., Seite 132-150 volume:43 year:2023 number:1 day:18 month:12 pages:132-150 |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR054273978</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240105064748.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240105s2023 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1038/s44318-023-00012-1</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR054273978</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s44318-023-00012-1-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Patel, Ashna</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0009-0008-4502-3990</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2023</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Understanding cellular decisions due to receptor–ligand interactions at cell–cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands—called CombiCells—to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor–ligand interactions at cell–cell interfaces.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis The inherent difficulty in manipulating cell surface proteins limits our ability to study cell–cell recognition. This work develops a platform for the combinatorial display of cell surface ligands (CombiCells), and demonstrates its value for determining the sensitivity and costimulatory requirements for T cells recognizing antigens on target cells. Proteins fused to SpyTag can be covalently coupled to the surfaces of cells expressing a membrane-anchored form of SpyCatcher.This enables rapid production of cells expressing different concentrations and combinations of multiple proteins, including antigens and accessory receptor ligands.Using CombiCells, the T cell receptor is found to be 10-fold more sensitive to its target ligand pMHC than CARs and BiTEs are to their target, CD19.By presenting T cells with Spytag-pMHC, PD-1 engagement is shown to promiscuously inhibit T cell activation in the presence or absence of CD2 or CD28 co-stimulation.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Expression of SpyCatcher on the cell surface allows tritration and combinatorial display of purified ligands fused to Spytag, enabling controlled investigation of receptor–ligand interactions at immune cell interfaces.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Receptor/Ligand Interactions</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cell–Cell Recognition</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Surface Ligand Presentation</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">T Cell Antigen Sensitivity</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Chimeric Antigen Receptors</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Andre, Violaine</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Eguiguren, Sofia Bustamante</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Barton, Michael I</subfield><subfield code="0">(orcid)0000-0002-9263-6481</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Burton, Jake</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Denham, Eleanor M</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Pettmann, Johannes</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Mørch, Alexander M</subfield><subfield code="0">(orcid)0000-0002-1881-2424</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Kutuzov, Mikhail A</subfield><subfield code="0">(orcid)0000-0003-3386-4350</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Siller-Farfán, Jesús A</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Dustin, Michael L</subfield><subfield code="0">(orcid)0000-0003-4983-6389</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">van der Merwe, P Anton</subfield><subfield code="0">(orcid)0000-0001-9902-6590</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Dushek, Omer</subfield><subfield code="0">(orcid)0000-0001-5847-5226</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">The EMBO Journal</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">43(2023), 1 vom: 18. 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|
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Patel, Ashna |
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Patel, Ashna misc Receptor/Ligand Interactions misc Cell–Cell Recognition misc Surface Ligand Presentation misc T Cell Antigen Sensitivity misc Chimeric Antigen Receptors Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors |
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Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors Receptor/Ligand Interactions (dpeaa)DE-He213 Cell–Cell Recognition (dpeaa)DE-He213 Surface Ligand Presentation (dpeaa)DE-He213 T Cell Antigen Sensitivity (dpeaa)DE-He213 Chimeric Antigen Receptors (dpeaa)DE-He213 |
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misc Receptor/Ligand Interactions misc Cell–Cell Recognition misc Surface Ligand Presentation misc T Cell Antigen Sensitivity misc Chimeric Antigen Receptors |
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misc Receptor/Ligand Interactions misc Cell–Cell Recognition misc Surface Ligand Presentation misc T Cell Antigen Sensitivity misc Chimeric Antigen Receptors |
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Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors |
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Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors |
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Patel, Ashna |
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Patel, Ashna Andre, Violaine Eguiguren, Sofia Bustamante Barton, Michael I Burton, Jake Denham, Eleanor M Pettmann, Johannes Mørch, Alexander M Kutuzov, Mikhail A Siller-Farfán, Jesús A Dustin, Michael L van der Merwe, P Anton Dushek, Omer |
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Elektronische Aufsätze |
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Patel, Ashna |
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10.1038/s44318-023-00012-1 |
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(ORCID)0009-0008-4502-3990 (ORCID)0000-0002-9263-6481 (ORCID)0000-0002-1881-2424 (ORCID)0000-0003-3386-4350 (ORCID)0000-0003-4983-6389 (ORCID)0000-0001-9902-6590 (ORCID)0000-0001-5847-5226 |
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using combicells, a platform for titration and combinatorial display of cell surface ligands, to study t-cell antigen sensitivity modulation by accessory receptors |
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Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors |
| abstract |
Abstract Understanding cellular decisions due to receptor–ligand interactions at cell–cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands—called CombiCells—to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor–ligand interactions at cell–cell interfaces. Synopsis The inherent difficulty in manipulating cell surface proteins limits our ability to study cell–cell recognition. This work develops a platform for the combinatorial display of cell surface ligands (CombiCells), and demonstrates its value for determining the sensitivity and costimulatory requirements for T cells recognizing antigens on target cells. Proteins fused to SpyTag can be covalently coupled to the surfaces of cells expressing a membrane-anchored form of SpyCatcher.This enables rapid production of cells expressing different concentrations and combinations of multiple proteins, including antigens and accessory receptor ligands.Using CombiCells, the T cell receptor is found to be 10-fold more sensitive to its target ligand pMHC than CARs and BiTEs are to their target, CD19.By presenting T cells with Spytag-pMHC, PD-1 engagement is shown to promiscuously inhibit T cell activation in the presence or absence of CD2 or CD28 co-stimulation. Expression of SpyCatcher on the cell surface allows tritration and combinatorial display of purified ligands fused to Spytag, enabling controlled investigation of receptor–ligand interactions at immune cell interfaces. © The Author(s) 2023 |
| abstractGer |
Abstract Understanding cellular decisions due to receptor–ligand interactions at cell–cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands—called CombiCells—to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor–ligand interactions at cell–cell interfaces. Synopsis The inherent difficulty in manipulating cell surface proteins limits our ability to study cell–cell recognition. This work develops a platform for the combinatorial display of cell surface ligands (CombiCells), and demonstrates its value for determining the sensitivity and costimulatory requirements for T cells recognizing antigens on target cells. Proteins fused to SpyTag can be covalently coupled to the surfaces of cells expressing a membrane-anchored form of SpyCatcher.This enables rapid production of cells expressing different concentrations and combinations of multiple proteins, including antigens and accessory receptor ligands.Using CombiCells, the T cell receptor is found to be 10-fold more sensitive to its target ligand pMHC than CARs and BiTEs are to their target, CD19.By presenting T cells with Spytag-pMHC, PD-1 engagement is shown to promiscuously inhibit T cell activation in the presence or absence of CD2 or CD28 co-stimulation. Expression of SpyCatcher on the cell surface allows tritration and combinatorial display of purified ligands fused to Spytag, enabling controlled investigation of receptor–ligand interactions at immune cell interfaces. © The Author(s) 2023 |
| abstract_unstemmed |
Abstract Understanding cellular decisions due to receptor–ligand interactions at cell–cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands—called CombiCells—to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor–ligand interactions at cell–cell interfaces. Synopsis The inherent difficulty in manipulating cell surface proteins limits our ability to study cell–cell recognition. This work develops a platform for the combinatorial display of cell surface ligands (CombiCells), and demonstrates its value for determining the sensitivity and costimulatory requirements for T cells recognizing antigens on target cells. Proteins fused to SpyTag can be covalently coupled to the surfaces of cells expressing a membrane-anchored form of SpyCatcher.This enables rapid production of cells expressing different concentrations and combinations of multiple proteins, including antigens and accessory receptor ligands.Using CombiCells, the T cell receptor is found to be 10-fold more sensitive to its target ligand pMHC than CARs and BiTEs are to their target, CD19.By presenting T cells with Spytag-pMHC, PD-1 engagement is shown to promiscuously inhibit T cell activation in the presence or absence of CD2 or CD28 co-stimulation. Expression of SpyCatcher on the cell surface allows tritration and combinatorial display of purified ligands fused to Spytag, enabling controlled investigation of receptor–ligand interactions at immune cell interfaces. © The Author(s) 2023 |
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Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors |
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| score |
7.4010057 |