Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells
Summary: Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Suwen Li [verfasserIn] Chloe S. Wang [verfasserIn] Amélie Montel-Hagen [verfasserIn] Ho-Chung Chen [verfasserIn] Shawn Lopez [verfasserIn] Olivia Zhou [verfasserIn] Kristy Dai [verfasserIn] Steven Tsai [verfasserIn] William Satyadi [verfasserIn] Carlos Botero [verfasserIn] Claudia Wong [verfasserIn] David Casero [verfasserIn] Gay M. Crooks [verfasserIn] Christopher S. Seet [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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| Übergeordnetes Werk: |
In: Cell Reports - Elsevier, 2015, 42(2023), 3, Seite 112241- |
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| Übergeordnetes Werk: |
volume:42 ; year:2023 ; number:3 ; pages:112241- |
| Links: |
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| DOI / URN: |
10.1016/j.celrep.2023.112241 |
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| Katalog-ID: |
DOAJ087928809 |
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| 245 | 1 | 0 | |a Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells |
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| 520 | |a Summary: Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs. | ||
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| 700 | 0 | |a Amélie Montel-Hagen |e verfasserin |4 aut | |
| 700 | 0 | |a Ho-Chung Chen |e verfasserin |4 aut | |
| 700 | 0 | |a Shawn Lopez |e verfasserin |4 aut | |
| 700 | 0 | |a Olivia Zhou |e verfasserin |4 aut | |
| 700 | 0 | |a Kristy Dai |e verfasserin |4 aut | |
| 700 | 0 | |a Steven Tsai |e verfasserin |4 aut | |
| 700 | 0 | |a William Satyadi |e verfasserin |4 aut | |
| 700 | 0 | |a Carlos Botero |e verfasserin |4 aut | |
| 700 | 0 | |a Claudia Wong |e verfasserin |4 aut | |
| 700 | 0 | |a David Casero |e verfasserin |4 aut | |
| 700 | 0 | |a Gay M. Crooks |e verfasserin |4 aut | |
| 700 | 0 | |a Christopher S. Seet |e verfasserin |4 aut | |
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10.1016/j.celrep.2023.112241 doi (DE-627)DOAJ087928809 (DE-599)DOAJ4cdfe5ceca0243298f94c0b20a002a90 DE-627 ger DE-627 rakwb eng QH301-705.5 Suwen Li verfasserin aut Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Summary: Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs. CP: Immunology CP: Stem cell research Biology (General) Chloe S. Wang verfasserin aut Amélie Montel-Hagen verfasserin aut Ho-Chung Chen verfasserin aut Shawn Lopez verfasserin aut Olivia Zhou verfasserin aut Kristy Dai verfasserin aut Steven Tsai verfasserin aut William Satyadi verfasserin aut Carlos Botero verfasserin aut Claudia Wong verfasserin aut David Casero verfasserin aut Gay M. Crooks verfasserin aut Christopher S. Seet verfasserin aut In Cell Reports Elsevier, 2015 42(2023), 3, Seite 112241- (DE-627)684964562 (DE-600)2649101-1 22111247 nnns volume:42 year:2023 number:3 pages:112241- https://doi.org/10.1016/j.celrep.2023.112241 kostenfrei https://doaj.org/article/4cdfe5ceca0243298f94c0b20a002a90 kostenfrei http://www.sciencedirect.com/science/article/pii/S2211124723002528 kostenfrei https://doaj.org/toc/2211-1247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 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_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 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_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 42 2023 3 112241- |
| spelling |
10.1016/j.celrep.2023.112241 doi (DE-627)DOAJ087928809 (DE-599)DOAJ4cdfe5ceca0243298f94c0b20a002a90 DE-627 ger DE-627 rakwb eng QH301-705.5 Suwen Li verfasserin aut Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Summary: Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs. CP: Immunology CP: Stem cell research Biology (General) Chloe S. Wang verfasserin aut Amélie Montel-Hagen verfasserin aut Ho-Chung Chen verfasserin aut Shawn Lopez verfasserin aut Olivia Zhou verfasserin aut Kristy Dai verfasserin aut Steven Tsai verfasserin aut William Satyadi verfasserin aut Carlos Botero verfasserin aut Claudia Wong verfasserin aut David Casero verfasserin aut Gay M. Crooks verfasserin aut Christopher S. Seet verfasserin aut In Cell Reports Elsevier, 2015 42(2023), 3, Seite 112241- (DE-627)684964562 (DE-600)2649101-1 22111247 nnns volume:42 year:2023 number:3 pages:112241- https://doi.org/10.1016/j.celrep.2023.112241 kostenfrei https://doaj.org/article/4cdfe5ceca0243298f94c0b20a002a90 kostenfrei http://www.sciencedirect.com/science/article/pii/S2211124723002528 kostenfrei https://doaj.org/toc/2211-1247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 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_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 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_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 42 2023 3 112241- |
| allfields_unstemmed |
10.1016/j.celrep.2023.112241 doi (DE-627)DOAJ087928809 (DE-599)DOAJ4cdfe5ceca0243298f94c0b20a002a90 DE-627 ger DE-627 rakwb eng QH301-705.5 Suwen Li verfasserin aut Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Summary: Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs. CP: Immunology CP: Stem cell research Biology (General) Chloe S. Wang verfasserin aut Amélie Montel-Hagen verfasserin aut Ho-Chung Chen verfasserin aut Shawn Lopez verfasserin aut Olivia Zhou verfasserin aut Kristy Dai verfasserin aut Steven Tsai verfasserin aut William Satyadi verfasserin aut Carlos Botero verfasserin aut Claudia Wong verfasserin aut David Casero verfasserin aut Gay M. Crooks verfasserin aut Christopher S. Seet verfasserin aut In Cell Reports Elsevier, 2015 42(2023), 3, Seite 112241- (DE-627)684964562 (DE-600)2649101-1 22111247 nnns volume:42 year:2023 number:3 pages:112241- https://doi.org/10.1016/j.celrep.2023.112241 kostenfrei https://doaj.org/article/4cdfe5ceca0243298f94c0b20a002a90 kostenfrei http://www.sciencedirect.com/science/article/pii/S2211124723002528 kostenfrei https://doaj.org/toc/2211-1247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 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_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 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_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 42 2023 3 112241- |
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10.1016/j.celrep.2023.112241 doi (DE-627)DOAJ087928809 (DE-599)DOAJ4cdfe5ceca0243298f94c0b20a002a90 DE-627 ger DE-627 rakwb eng QH301-705.5 Suwen Li verfasserin aut Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Summary: Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs. CP: Immunology CP: Stem cell research Biology (General) Chloe S. Wang verfasserin aut Amélie Montel-Hagen verfasserin aut Ho-Chung Chen verfasserin aut Shawn Lopez verfasserin aut Olivia Zhou verfasserin aut Kristy Dai verfasserin aut Steven Tsai verfasserin aut William Satyadi verfasserin aut Carlos Botero verfasserin aut Claudia Wong verfasserin aut David Casero verfasserin aut Gay M. Crooks verfasserin aut Christopher S. Seet verfasserin aut In Cell Reports Elsevier, 2015 42(2023), 3, Seite 112241- (DE-627)684964562 (DE-600)2649101-1 22111247 nnns volume:42 year:2023 number:3 pages:112241- https://doi.org/10.1016/j.celrep.2023.112241 kostenfrei https://doaj.org/article/4cdfe5ceca0243298f94c0b20a002a90 kostenfrei http://www.sciencedirect.com/science/article/pii/S2211124723002528 kostenfrei https://doaj.org/toc/2211-1247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 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_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 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_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 42 2023 3 112241- |
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Suwen Li @@aut@@ Chloe S. Wang @@aut@@ Amélie Montel-Hagen @@aut@@ Ho-Chung Chen @@aut@@ Shawn Lopez @@aut@@ Olivia Zhou @@aut@@ Kristy Dai @@aut@@ Steven Tsai @@aut@@ William Satyadi @@aut@@ Carlos Botero @@aut@@ Claudia Wong @@aut@@ David Casero @@aut@@ Gay M. Crooks @@aut@@ Christopher S. Seet @@aut@@ |
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Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells |
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Summary: Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs. |
| abstractGer |
Summary: Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs. |
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Summary: Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs. |
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