Combinatorial genetic engineering strategy for immune protection of stem cell-derived beta cells by chimeric antigen receptor regulatory T cells
Regenerative medicine is a rapidly expanding field harnessing human pluripotent stem cell (hPSC)-derived cells and tissues to treat many diseases, including type 1 diabetes. However, graft immune protection remains a key challenge. Chimeric antigen receptor (CAR) technology confers new specificities...
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| Veröffentlicht in: | Cell reports (Cambridge) 2024-11, Vol.43 (11), p.114994, Article 114994 |
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| creator | Barra, Jessie M. Robino, Rob A. Castro-Gutierrez, Roberto Proia, James Russ, Holger A. Ferreira, Leonardo M.R. |
| description | Regenerative medicine is a rapidly expanding field harnessing human pluripotent stem cell (hPSC)-derived cells and tissues to treat many diseases, including type 1 diabetes. However, graft immune protection remains a key challenge. Chimeric antigen receptor (CAR) technology confers new specificities to effector T cells and immunosuppressive regulatory T cells (Tregs). One challenge in CAR design is identifying target molecules unique to the cells of interest. Here, we employ combinatorial genetic engineering to confer CAR-Treg-mediated localized immune protection to stem cell-derived cells. We engineered hPSCs to express truncated epidermal growth factor receptor (EGFRt), a biologically inert and generalizable target for CAR-Treg homing and activation, and generated CAR-Tregs recognizing EGFRt. Strikingly, CAR-Tregs suppressed innate and adaptive immune responses in vitro and prevented EGFRt-hPSC-derived pancreatic beta-like cell (sBC [stem cell-derived beta cell]) graft immune destruction in vivo. Collectively, we provide proof of concept that hPSCs and Tregs can be co-engineered to protect hPSC-derived cells from immune rejection upon transplantation.
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•Gene editing of human pluripotent stem cells (hPSCs) to express unique bait protein•Regulatory T cell engineering with bait-specific chimeric antigen receptor (CAR-Treg)•CAR-Tregs are suppressive in vitro when activated by bait-expressing cells•CAR-Tregs protect bait-expressing hPSC-derived beta cells from immune destruction in vivo
Immune protection of human pluripotent stem cell (hPSC)-derived grafts remains a key hurdle in regenerative medicine. Barra and Robino et al. engineered hPSCs to express an inert bait protein and bait-specific immunosuppressive chimeric antigen receptor regulatory T cells (CAR-Tregs), accomplishing localized hPSC-derived beta cell immune protection in humanized mice. |
| doi_str_mv | 10.1016/j.celrep.2024.114994 |
| format | Article |
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[Display omitted]
•Gene editing of human pluripotent stem cells (hPSCs) to express unique bait protein•Regulatory T cell engineering with bait-specific chimeric antigen receptor (CAR-Treg)•CAR-Tregs are suppressive in vitro when activated by bait-expressing cells•CAR-Tregs protect bait-expressing hPSC-derived beta cells from immune destruction in vivo
Immune protection of human pluripotent stem cell (hPSC)-derived grafts remains a key hurdle in regenerative medicine. Barra and Robino et al. engineered hPSCs to express an inert bait protein and bait-specific immunosuppressive chimeric antigen receptor regulatory T cells (CAR-Tregs), accomplishing localized hPSC-derived beta cell immune protection in humanized mice.</description><identifier>ISSN: 2211-1247</identifier><identifier>EISSN: 2211-1247</identifier><identifier>DOI: 10.1016/j.celrep.2024.114994</identifier><identifier>PMID: 39561045</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; autoimmunity ; CAR-Treg ; cell replacement therapy ; chimeric antigen receptor ; ErbB Receptors - metabolism ; Genetic Engineering - methods ; Humans ; immune tolerance ; Insulin-Secreting Cells - immunology ; Insulin-Secreting Cells - metabolism ; Mice ; Mice, Inbred NOD ; Pluripotent Stem Cells - cytology ; Pluripotent Stem Cells - metabolism ; Receptors, Chimeric Antigen - immunology ; Receptors, Chimeric Antigen - metabolism ; regenerative medicine ; regulatory T cell ; stem cell-derived beta cell ; T-Lymphocytes, Regulatory - immunology ; transplantation ; type 1 diabetes</subject><ispartof>Cell reports (Cambridge), 2024-11, Vol.43 (11), p.114994, Article 114994</ispartof><rights>2024 The Authors</rights><rights>Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c287t-3f78c94bcfcf3d0f01ffc8ab2b4008718e792da85f78372c39c3f592f5767ed43</cites><orcidid>0000-0003-2491-9866</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,865,27926,27927</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39561045$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Barra, Jessie M.</creatorcontrib><creatorcontrib>Robino, Rob A.</creatorcontrib><creatorcontrib>Castro-Gutierrez, Roberto</creatorcontrib><creatorcontrib>Proia, James</creatorcontrib><creatorcontrib>Russ, Holger A.</creatorcontrib><creatorcontrib>Ferreira, Leonardo M.R.</creatorcontrib><title>Combinatorial genetic engineering strategy for immune protection of stem cell-derived beta cells by chimeric antigen receptor regulatory T cells</title><title>Cell reports (Cambridge)</title><addtitle>Cell Rep</addtitle><description>Regenerative medicine is a rapidly expanding field harnessing human pluripotent stem cell (hPSC)-derived cells and tissues to treat many diseases, including type 1 diabetes. However, graft immune protection remains a key challenge. Chimeric antigen receptor (CAR) technology confers new specificities to effector T cells and immunosuppressive regulatory T cells (Tregs). One challenge in CAR design is identifying target molecules unique to the cells of interest. Here, we employ combinatorial genetic engineering to confer CAR-Treg-mediated localized immune protection to stem cell-derived cells. We engineered hPSCs to express truncated epidermal growth factor receptor (EGFRt), a biologically inert and generalizable target for CAR-Treg homing and activation, and generated CAR-Tregs recognizing EGFRt. Strikingly, CAR-Tregs suppressed innate and adaptive immune responses in vitro and prevented EGFRt-hPSC-derived pancreatic beta-like cell (sBC [stem cell-derived beta cell]) graft immune destruction in vivo. Collectively, we provide proof of concept that hPSCs and Tregs can be co-engineered to protect hPSC-derived cells from immune rejection upon transplantation.
[Display omitted]
•Gene editing of human pluripotent stem cells (hPSCs) to express unique bait protein•Regulatory T cell engineering with bait-specific chimeric antigen receptor (CAR-Treg)•CAR-Tregs are suppressive in vitro when activated by bait-expressing cells•CAR-Tregs protect bait-expressing hPSC-derived beta cells from immune destruction in vivo
Immune protection of human pluripotent stem cell (hPSC)-derived grafts remains a key hurdle in regenerative medicine. Barra and Robino et al. engineered hPSCs to express an inert bait protein and bait-specific immunosuppressive chimeric antigen receptor regulatory T cells (CAR-Tregs), accomplishing localized hPSC-derived beta cell immune protection in humanized mice.</description><subject>Animals</subject><subject>autoimmunity</subject><subject>CAR-Treg</subject><subject>cell replacement therapy</subject><subject>chimeric antigen receptor</subject><subject>ErbB Receptors - metabolism</subject><subject>Genetic Engineering - methods</subject><subject>Humans</subject><subject>immune tolerance</subject><subject>Insulin-Secreting Cells - immunology</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Pluripotent Stem Cells - cytology</subject><subject>Pluripotent Stem Cells - metabolism</subject><subject>Receptors, Chimeric Antigen - immunology</subject><subject>Receptors, Chimeric Antigen - metabolism</subject><subject>regenerative medicine</subject><subject>regulatory T cell</subject><subject>stem cell-derived beta cell</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>transplantation</subject><subject>type 1 diabetes</subject><issn>2211-1247</issn><issn>2211-1247</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtuHCEURVHkKLY63kFkMcyk2vzqwyRS1HI-kqVMnDGiqEeFVhW0gbLUy_AOshavLLTLiTwKExCcy33vXYQ-ULKlhDbX-62BKcJhywgTW0qFlOINumCM0ooy0Z69Op-jy5T2pKyGUCrFO3TOZd1QIuoL9LgLc--8ziE6PeERPGRnMPjReYDo_IhTjjrDeMQ2ROzmefGADzFkMNkFj4MtBMy4FDRVQ5E8wIB7yPr5JuH-iM0vN5cHg7XPrljgCAYOxbIcxmU6mR_x3dPvZ8F79NbqKcHly75BP7_c3O2-Vbc_vn7ffb6tDOvaXHHbdkaK3lhj-UAsodaaTvesF4R0Le2glWzQXV043jLDpeG2lszWbdPCIPgGfVz_Lb3cL5Cyml06VaA9hCUpTjnpWEdkU1CxoiaGlCJYdYhu1vGoKFGnPNRerXmoUx5qzaPIrl4cln6G4Z_o7_QL8GkFoPT54CCqZBx4A4MrE8pqCO7_Dn8AV1Oh2Q</recordid><startdate>20241126</startdate><enddate>20241126</enddate><creator>Barra, Jessie M.</creator><creator>Robino, Rob A.</creator><creator>Castro-Gutierrez, Roberto</creator><creator>Proia, James</creator><creator>Russ, Holger A.</creator><creator>Ferreira, Leonardo M.R.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2491-9866</orcidid></search><sort><creationdate>20241126</creationdate><title>Combinatorial genetic engineering strategy for immune protection of stem cell-derived beta cells by chimeric antigen receptor regulatory T cells</title><author>Barra, Jessie M. ; Robino, Rob A. ; Castro-Gutierrez, Roberto ; Proia, James ; Russ, Holger A. ; Ferreira, Leonardo M.R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c287t-3f78c94bcfcf3d0f01ffc8ab2b4008718e792da85f78372c39c3f592f5767ed43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>autoimmunity</topic><topic>CAR-Treg</topic><topic>cell replacement therapy</topic><topic>chimeric antigen receptor</topic><topic>ErbB Receptors - metabolism</topic><topic>Genetic Engineering - methods</topic><topic>Humans</topic><topic>immune tolerance</topic><topic>Insulin-Secreting Cells - immunology</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Pluripotent Stem Cells - cytology</topic><topic>Pluripotent Stem Cells - metabolism</topic><topic>Receptors, Chimeric Antigen - immunology</topic><topic>Receptors, Chimeric Antigen - metabolism</topic><topic>regenerative medicine</topic><topic>regulatory T cell</topic><topic>stem cell-derived beta cell</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>transplantation</topic><topic>type 1 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barra, Jessie M.</creatorcontrib><creatorcontrib>Robino, Rob A.</creatorcontrib><creatorcontrib>Castro-Gutierrez, Roberto</creatorcontrib><creatorcontrib>Proia, James</creatorcontrib><creatorcontrib>Russ, Holger A.</creatorcontrib><creatorcontrib>Ferreira, Leonardo M.R.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cell reports (Cambridge)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Barra, Jessie M.</au><au>Robino, Rob A.</au><au>Castro-Gutierrez, Roberto</au><au>Proia, James</au><au>Russ, Holger A.</au><au>Ferreira, Leonardo M.R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combinatorial genetic engineering strategy for immune protection of stem cell-derived beta cells by chimeric antigen receptor regulatory T cells</atitle><jtitle>Cell reports (Cambridge)</jtitle><addtitle>Cell Rep</addtitle><date>2024-11-26</date><risdate>2024</risdate><volume>43</volume><issue>11</issue><spage>114994</spage><pages>114994-</pages><artnum>114994</artnum><issn>2211-1247</issn><eissn>2211-1247</eissn><abstract>Regenerative medicine is a rapidly expanding field harnessing human pluripotent stem cell (hPSC)-derived cells and tissues to treat many diseases, including type 1 diabetes. However, graft immune protection remains a key challenge. Chimeric antigen receptor (CAR) technology confers new specificities to effector T cells and immunosuppressive regulatory T cells (Tregs). One challenge in CAR design is identifying target molecules unique to the cells of interest. Here, we employ combinatorial genetic engineering to confer CAR-Treg-mediated localized immune protection to stem cell-derived cells. We engineered hPSCs to express truncated epidermal growth factor receptor (EGFRt), a biologically inert and generalizable target for CAR-Treg homing and activation, and generated CAR-Tregs recognizing EGFRt. Strikingly, CAR-Tregs suppressed innate and adaptive immune responses in vitro and prevented EGFRt-hPSC-derived pancreatic beta-like cell (sBC [stem cell-derived beta cell]) graft immune destruction in vivo. Collectively, we provide proof of concept that hPSCs and Tregs can be co-engineered to protect hPSC-derived cells from immune rejection upon transplantation.
[Display omitted]
•Gene editing of human pluripotent stem cells (hPSCs) to express unique bait protein•Regulatory T cell engineering with bait-specific chimeric antigen receptor (CAR-Treg)•CAR-Tregs are suppressive in vitro when activated by bait-expressing cells•CAR-Tregs protect bait-expressing hPSC-derived beta cells from immune destruction in vivo
Immune protection of human pluripotent stem cell (hPSC)-derived grafts remains a key hurdle in regenerative medicine. Barra and Robino et al. engineered hPSCs to express an inert bait protein and bait-specific immunosuppressive chimeric antigen receptor regulatory T cells (CAR-Tregs), accomplishing localized hPSC-derived beta cell immune protection in humanized mice.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>39561045</pmid><doi>10.1016/j.celrep.2024.114994</doi><orcidid>https://orcid.org/0000-0003-2491-9866</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Cell Press Free Archives; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Animals autoimmunity CAR-Treg cell replacement therapy chimeric antigen receptor ErbB Receptors - metabolism Genetic Engineering - methods Humans immune tolerance Insulin-Secreting Cells - immunology Insulin-Secreting Cells - metabolism Mice Mice, Inbred NOD Pluripotent Stem Cells - cytology Pluripotent Stem Cells - metabolism Receptors, Chimeric Antigen - immunology Receptors, Chimeric Antigen - metabolism regenerative medicine regulatory T cell stem cell-derived beta cell T-Lymphocytes, Regulatory - immunology transplantation type 1 diabetes |
| title | Combinatorial genetic engineering strategy for immune protection of stem cell-derived beta cells by chimeric antigen receptor regulatory T cells |
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