Human‐engineered Treg‐like cells suppress FOXP3‐deficient T cells but preserve adaptive immune responses in vivo
Objectives Genetic or acquired defects in FOXP3+ regulatory T cells (Tregs) play a key role in many immune‐mediated diseases including immune dysregulation polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome. Previously, we demonstrated CD4+ T cells from healthy donors and IPEX patients can be...
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Veröffentlicht in: | Clinical & translational immunology 2020, Vol.9 (11), p.e1214-n/a |
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creator | Sato, Yohei Passerini, Laura Piening, Brian D Uyeda, Molly Javier Goodwin, Marianne Gregori, Silvia Snyder, Michael P Bertaina, Alice Roncarolo, Maria‐Grazia Bacchetta, Rosa |
description | Objectives
Genetic or acquired defects in FOXP3+ regulatory T cells (Tregs) play a key role in many immune‐mediated diseases including immune dysregulation polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome. Previously, we demonstrated CD4+ T cells from healthy donors and IPEX patients can be converted into functional Treg‐like cells by lentiviral transfer of FOXP3 (CD4LVFOXP3). These CD4LVFOXP3 cells have potent regulatory function, suggesting their potential as an innovative therapeutic. Here, we present molecular and preclinical in vivo data supporting CD4LVFOXP3 cell clinical progression.
Methods
The molecular characterisation of CD4LVFOXP3 cells included flow cytometry, qPCR, RNA‐seq and TCR‐seq. The in vivo suppressive function of CD4LVFOXP3 cells was assessed in xenograft‐versus‐host disease (xeno‐GvHD) and FOXP3‐deficient IPEX‐like humanised mouse models. The safety of CD4LVFOXP3 cells was evaluated using peripheral blood (PB) humanised (hu)‐ mice testing their impact on immune response against pathogens, and immune surveillance against tumor antigens.
Results
We demonstrate that the conversion of CD4+ T cells to CD4LVFOXP3 cells leads to specific transcriptional changes as compared to CD4+ T‐cell transduction in the absence of FOXP3, including upregulation of Treg‐related genes. Furthermore, we observe specific preservation of a polyclonal TCR repertoire during in vitro cell production. Both allogeneic and autologous CD4LVFOXP3 cells protect from xeno‐GvHD after two sequential infusions of effector T cells. CD4LVFOXP3 cells prevent hyper‐proliferation of CD4+ memory T cells in the FOXP3‐deficient IPEX‐like hu‐mice. CD4LVFOXP3 cells do not impede in vivo expansion of antigen‐primed T cells or tumor clearance in the PB hu‐mice.
Conclusion
These data support the clinical readiness of CD4LVFOXP3 cells to treat IPEX syndrome and other immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs.
In this study, we present novel molecular and preclinical in vivo data that support CD4LVFOXP3 clinical progression. These data support the clinical readiness of CD4LVFOXP3 to treat immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs. |
doi_str_mv | 10.1002/cti2.1214 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7688376</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2464539305</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4434-682014248dfedaa0e463eaa8344f584240c314a3e7a015f6d325355de1a497ab3</originalsourceid><addsrcrecordid>eNp1kcFu1DAQhi0EotXSAy-ALHGBw7Zjj511L0hoRWmlSuWwSNwsbzJZXBIn2ElQbzwCz8iT4LBLVZA4eTT_p1__-GfsuYBTASDPysHLUyGFesSOJWhYAhTm8YP5iJ2kdAsAAhVoUTxlR4gIShs8ZtPl2Lrw8_sPCjsfiCJVfBNplzeN_0K8pKZJPI19HyklfnHz6QNmraLal57CwDcHZDsOfGYoTsRd5frB58G37RiI533fhUSJ-8AnP3XP2JPaNYlODu-Cfbx4t1lfLq9v3l-t314vS6VQLQsjQSipTFVT5RyQKpCcM6hUrU0WoEShHNLKgdB1UaHUqHVFwqnzldvigr3Z-_bjtqWqzImja2wffevine2ct38rwX-2u26yq8IYXBXZ4NXBIHZfR0qDbX2aL3aBujHZnC3_qpGZXrCX_6C33RhDPi9ThdJ4jqAz9XpPlbFLKVJ9H0aAnQu1c6F2LjSzLx6mvyf_1JeBsz3wzTd0938nu95cyd-WvwAgB63Y</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2464539305</pqid></control><display><type>article</type><title>Human‐engineered Treg‐like cells suppress FOXP3‐deficient T cells but preserve adaptive immune responses in vivo</title><source>DOAJ Directory of Open Access Journals</source><source>Access via Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Wiley Online Library (Open Access Collection)</source><source>PubMed Central</source><creator>Sato, Yohei ; Passerini, Laura ; Piening, Brian D ; Uyeda, Molly Javier ; Goodwin, Marianne ; Gregori, Silvia ; Snyder, Michael P ; Bertaina, Alice ; Roncarolo, Maria‐Grazia ; Bacchetta, Rosa</creator><creatorcontrib>Sato, Yohei ; Passerini, Laura ; Piening, Brian D ; Uyeda, Molly Javier ; Goodwin, Marianne ; Gregori, Silvia ; Snyder, Michael P ; Bertaina, Alice ; Roncarolo, Maria‐Grazia ; Bacchetta, Rosa</creatorcontrib><description>Objectives
Genetic or acquired defects in FOXP3+ regulatory T cells (Tregs) play a key role in many immune‐mediated diseases including immune dysregulation polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome. Previously, we demonstrated CD4+ T cells from healthy donors and IPEX patients can be converted into functional Treg‐like cells by lentiviral transfer of FOXP3 (CD4LVFOXP3). These CD4LVFOXP3 cells have potent regulatory function, suggesting their potential as an innovative therapeutic. Here, we present molecular and preclinical in vivo data supporting CD4LVFOXP3 cell clinical progression.
Methods
The molecular characterisation of CD4LVFOXP3 cells included flow cytometry, qPCR, RNA‐seq and TCR‐seq. The in vivo suppressive function of CD4LVFOXP3 cells was assessed in xenograft‐versus‐host disease (xeno‐GvHD) and FOXP3‐deficient IPEX‐like humanised mouse models. The safety of CD4LVFOXP3 cells was evaluated using peripheral blood (PB) humanised (hu)‐ mice testing their impact on immune response against pathogens, and immune surveillance against tumor antigens.
Results
We demonstrate that the conversion of CD4+ T cells to CD4LVFOXP3 cells leads to specific transcriptional changes as compared to CD4+ T‐cell transduction in the absence of FOXP3, including upregulation of Treg‐related genes. Furthermore, we observe specific preservation of a polyclonal TCR repertoire during in vitro cell production. Both allogeneic and autologous CD4LVFOXP3 cells protect from xeno‐GvHD after two sequential infusions of effector T cells. CD4LVFOXP3 cells prevent hyper‐proliferation of CD4+ memory T cells in the FOXP3‐deficient IPEX‐like hu‐mice. CD4LVFOXP3 cells do not impede in vivo expansion of antigen‐primed T cells or tumor clearance in the PB hu‐mice.
Conclusion
These data support the clinical readiness of CD4LVFOXP3 cells to treat IPEX syndrome and other immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs.
In this study, we present novel molecular and preclinical in vivo data that support CD4LVFOXP3 clinical progression. These data support the clinical readiness of CD4LVFOXP3 to treat immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs.</description><identifier>ISSN: 2050-0068</identifier><identifier>EISSN: 2050-0068</identifier><identifier>DOI: 10.1002/cti2.1214</identifier><identifier>PMID: 33304583</identifier><language>eng</language><publisher>Australia: John Wiley & Sons, Inc</publisher><subject>Adaptive immunity ; Animal models ; Antigen (tumor-associated) ; Antigens ; CD4 antigen ; Cell proliferation ; CRISPR/Cas9 ; Cytokines ; Disease ; Effector cells ; Flow cytometry ; FOXP3 ; Foxp3 protein ; Gene expression ; gene therapy ; Genetic engineering ; Genotype & phenotype ; Graft-versus-host reaction ; Immune clearance ; Immunological memory ; Immunoregulation ; Immunosurveillance ; IPEX syndrome ; lentiviral vector ; Lymphocytes ; Lymphocytes T ; Medical innovations ; Medical prognosis ; Memory cells ; Original ; Patients ; Peripheral blood ; regulatory T cells ; Ribonucleic acid ; RNA ; T cell receptors ; Transcription ; Xenografts</subject><ispartof>Clinical & translational immunology, 2020, Vol.9 (11), p.e1214-n/a</ispartof><rights>2020 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.</rights><rights>2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.</rights><rights>2020. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4434-682014248dfedaa0e463eaa8344f584240c314a3e7a015f6d325355de1a497ab3</citedby><cites>FETCH-LOGICAL-c4434-682014248dfedaa0e463eaa8344f584240c314a3e7a015f6d325355de1a497ab3</cites><orcidid>0000-0002-8042-0069</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688376/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688376/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1417,4024,11562,27923,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33304583$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sato, Yohei</creatorcontrib><creatorcontrib>Passerini, Laura</creatorcontrib><creatorcontrib>Piening, Brian D</creatorcontrib><creatorcontrib>Uyeda, Molly Javier</creatorcontrib><creatorcontrib>Goodwin, Marianne</creatorcontrib><creatorcontrib>Gregori, Silvia</creatorcontrib><creatorcontrib>Snyder, Michael P</creatorcontrib><creatorcontrib>Bertaina, Alice</creatorcontrib><creatorcontrib>Roncarolo, Maria‐Grazia</creatorcontrib><creatorcontrib>Bacchetta, Rosa</creatorcontrib><title>Human‐engineered Treg‐like cells suppress FOXP3‐deficient T cells but preserve adaptive immune responses in vivo</title><title>Clinical & translational immunology</title><addtitle>Clin Transl Immunology</addtitle><description>Objectives
Genetic or acquired defects in FOXP3+ regulatory T cells (Tregs) play a key role in many immune‐mediated diseases including immune dysregulation polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome. Previously, we demonstrated CD4+ T cells from healthy donors and IPEX patients can be converted into functional Treg‐like cells by lentiviral transfer of FOXP3 (CD4LVFOXP3). These CD4LVFOXP3 cells have potent regulatory function, suggesting their potential as an innovative therapeutic. Here, we present molecular and preclinical in vivo data supporting CD4LVFOXP3 cell clinical progression.
Methods
The molecular characterisation of CD4LVFOXP3 cells included flow cytometry, qPCR, RNA‐seq and TCR‐seq. The in vivo suppressive function of CD4LVFOXP3 cells was assessed in xenograft‐versus‐host disease (xeno‐GvHD) and FOXP3‐deficient IPEX‐like humanised mouse models. The safety of CD4LVFOXP3 cells was evaluated using peripheral blood (PB) humanised (hu)‐ mice testing their impact on immune response against pathogens, and immune surveillance against tumor antigens.
Results
We demonstrate that the conversion of CD4+ T cells to CD4LVFOXP3 cells leads to specific transcriptional changes as compared to CD4+ T‐cell transduction in the absence of FOXP3, including upregulation of Treg‐related genes. Furthermore, we observe specific preservation of a polyclonal TCR repertoire during in vitro cell production. Both allogeneic and autologous CD4LVFOXP3 cells protect from xeno‐GvHD after two sequential infusions of effector T cells. CD4LVFOXP3 cells prevent hyper‐proliferation of CD4+ memory T cells in the FOXP3‐deficient IPEX‐like hu‐mice. CD4LVFOXP3 cells do not impede in vivo expansion of antigen‐primed T cells or tumor clearance in the PB hu‐mice.
Conclusion
These data support the clinical readiness of CD4LVFOXP3 cells to treat IPEX syndrome and other immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs.
In this study, we present novel molecular and preclinical in vivo data that support CD4LVFOXP3 clinical progression. These data support the clinical readiness of CD4LVFOXP3 to treat immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs.</description><subject>Adaptive immunity</subject><subject>Animal models</subject><subject>Antigen (tumor-associated)</subject><subject>Antigens</subject><subject>CD4 antigen</subject><subject>Cell proliferation</subject><subject>CRISPR/Cas9</subject><subject>Cytokines</subject><subject>Disease</subject><subject>Effector cells</subject><subject>Flow cytometry</subject><subject>FOXP3</subject><subject>Foxp3 protein</subject><subject>Gene expression</subject><subject>gene therapy</subject><subject>Genetic engineering</subject><subject>Genotype & phenotype</subject><subject>Graft-versus-host reaction</subject><subject>Immune clearance</subject><subject>Immunological memory</subject><subject>Immunoregulation</subject><subject>Immunosurveillance</subject><subject>IPEX syndrome</subject><subject>lentiviral vector</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Medical innovations</subject><subject>Medical prognosis</subject><subject>Memory cells</subject><subject>Original</subject><subject>Patients</subject><subject>Peripheral blood</subject><subject>regulatory T cells</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>T cell receptors</subject><subject>Transcription</subject><subject>Xenografts</subject><issn>2050-0068</issn><issn>2050-0068</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kcFu1DAQhi0EotXSAy-ALHGBw7Zjj511L0hoRWmlSuWwSNwsbzJZXBIn2ElQbzwCz8iT4LBLVZA4eTT_p1__-GfsuYBTASDPysHLUyGFesSOJWhYAhTm8YP5iJ2kdAsAAhVoUTxlR4gIShs8ZtPl2Lrw8_sPCjsfiCJVfBNplzeN_0K8pKZJPI19HyklfnHz6QNmraLal57CwDcHZDsOfGYoTsRd5frB58G37RiI533fhUSJ-8AnP3XP2JPaNYlODu-Cfbx4t1lfLq9v3l-t314vS6VQLQsjQSipTFVT5RyQKpCcM6hUrU0WoEShHNLKgdB1UaHUqHVFwqnzldvigr3Z-_bjtqWqzImja2wffevine2ct38rwX-2u26yq8IYXBXZ4NXBIHZfR0qDbX2aL3aBujHZnC3_qpGZXrCX_6C33RhDPi9ThdJ4jqAz9XpPlbFLKVJ9H0aAnQu1c6F2LjSzLx6mvyf_1JeBsz3wzTd0938nu95cyd-WvwAgB63Y</recordid><startdate>2020</startdate><enddate>2020</enddate><creator>Sato, Yohei</creator><creator>Passerini, Laura</creator><creator>Piening, Brian D</creator><creator>Uyeda, Molly Javier</creator><creator>Goodwin, Marianne</creator><creator>Gregori, Silvia</creator><creator>Snyder, Michael P</creator><creator>Bertaina, Alice</creator><creator>Roncarolo, Maria‐Grazia</creator><creator>Bacchetta, Rosa</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8042-0069</orcidid></search><sort><creationdate>2020</creationdate><title>Human‐engineered Treg‐like cells suppress FOXP3‐deficient T cells but preserve adaptive immune responses in vivo</title><author>Sato, Yohei ; Passerini, Laura ; Piening, Brian D ; Uyeda, Molly Javier ; Goodwin, Marianne ; Gregori, Silvia ; Snyder, Michael P ; Bertaina, Alice ; Roncarolo, Maria‐Grazia ; Bacchetta, Rosa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4434-682014248dfedaa0e463eaa8344f584240c314a3e7a015f6d325355de1a497ab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adaptive immunity</topic><topic>Animal models</topic><topic>Antigen (tumor-associated)</topic><topic>Antigens</topic><topic>CD4 antigen</topic><topic>Cell proliferation</topic><topic>CRISPR/Cas9</topic><topic>Cytokines</topic><topic>Disease</topic><topic>Effector cells</topic><topic>Flow cytometry</topic><topic>FOXP3</topic><topic>Foxp3 protein</topic><topic>Gene expression</topic><topic>gene therapy</topic><topic>Genetic engineering</topic><topic>Genotype & phenotype</topic><topic>Graft-versus-host reaction</topic><topic>Immune clearance</topic><topic>Immunological memory</topic><topic>Immunoregulation</topic><topic>Immunosurveillance</topic><topic>IPEX syndrome</topic><topic>lentiviral vector</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Medical innovations</topic><topic>Medical prognosis</topic><topic>Memory cells</topic><topic>Original</topic><topic>Patients</topic><topic>Peripheral blood</topic><topic>regulatory T cells</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>T cell receptors</topic><topic>Transcription</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sato, Yohei</creatorcontrib><creatorcontrib>Passerini, Laura</creatorcontrib><creatorcontrib>Piening, Brian D</creatorcontrib><creatorcontrib>Uyeda, Molly Javier</creatorcontrib><creatorcontrib>Goodwin, Marianne</creatorcontrib><creatorcontrib>Gregori, Silvia</creatorcontrib><creatorcontrib>Snyder, Michael P</creatorcontrib><creatorcontrib>Bertaina, Alice</creatorcontrib><creatorcontrib>Roncarolo, Maria‐Grazia</creatorcontrib><creatorcontrib>Bacchetta, Rosa</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical & translational immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sato, Yohei</au><au>Passerini, Laura</au><au>Piening, Brian D</au><au>Uyeda, Molly Javier</au><au>Goodwin, Marianne</au><au>Gregori, Silvia</au><au>Snyder, Michael P</au><au>Bertaina, Alice</au><au>Roncarolo, Maria‐Grazia</au><au>Bacchetta, Rosa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human‐engineered Treg‐like cells suppress FOXP3‐deficient T cells but preserve adaptive immune responses in vivo</atitle><jtitle>Clinical & translational immunology</jtitle><addtitle>Clin Transl Immunology</addtitle><date>2020</date><risdate>2020</risdate><volume>9</volume><issue>11</issue><spage>e1214</spage><epage>n/a</epage><pages>e1214-n/a</pages><issn>2050-0068</issn><eissn>2050-0068</eissn><abstract>Objectives
Genetic or acquired defects in FOXP3+ regulatory T cells (Tregs) play a key role in many immune‐mediated diseases including immune dysregulation polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome. Previously, we demonstrated CD4+ T cells from healthy donors and IPEX patients can be converted into functional Treg‐like cells by lentiviral transfer of FOXP3 (CD4LVFOXP3). These CD4LVFOXP3 cells have potent regulatory function, suggesting their potential as an innovative therapeutic. Here, we present molecular and preclinical in vivo data supporting CD4LVFOXP3 cell clinical progression.
Methods
The molecular characterisation of CD4LVFOXP3 cells included flow cytometry, qPCR, RNA‐seq and TCR‐seq. The in vivo suppressive function of CD4LVFOXP3 cells was assessed in xenograft‐versus‐host disease (xeno‐GvHD) and FOXP3‐deficient IPEX‐like humanised mouse models. The safety of CD4LVFOXP3 cells was evaluated using peripheral blood (PB) humanised (hu)‐ mice testing their impact on immune response against pathogens, and immune surveillance against tumor antigens.
Results
We demonstrate that the conversion of CD4+ T cells to CD4LVFOXP3 cells leads to specific transcriptional changes as compared to CD4+ T‐cell transduction in the absence of FOXP3, including upregulation of Treg‐related genes. Furthermore, we observe specific preservation of a polyclonal TCR repertoire during in vitro cell production. Both allogeneic and autologous CD4LVFOXP3 cells protect from xeno‐GvHD after two sequential infusions of effector T cells. CD4LVFOXP3 cells prevent hyper‐proliferation of CD4+ memory T cells in the FOXP3‐deficient IPEX‐like hu‐mice. CD4LVFOXP3 cells do not impede in vivo expansion of antigen‐primed T cells or tumor clearance in the PB hu‐mice.
Conclusion
These data support the clinical readiness of CD4LVFOXP3 cells to treat IPEX syndrome and other immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs.
In this study, we present novel molecular and preclinical in vivo data that support CD4LVFOXP3 clinical progression. These data support the clinical readiness of CD4LVFOXP3 to treat immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs.</abstract><cop>Australia</cop><pub>John Wiley & Sons, Inc</pub><pmid>33304583</pmid><doi>10.1002/cti2.1214</doi><tpages>23</tpages><orcidid>https://orcid.org/0000-0002-8042-0069</orcidid><oa>free_for_read</oa></addata></record> |
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source | DOAJ Directory of Open Access Journals; Access via Wiley Online Library; EZB-FREE-00999 freely available EZB journals; Wiley Online Library (Open Access Collection); PubMed Central |
subjects | Adaptive immunity Animal models Antigen (tumor-associated) Antigens CD4 antigen Cell proliferation CRISPR/Cas9 Cytokines Disease Effector cells Flow cytometry FOXP3 Foxp3 protein Gene expression gene therapy Genetic engineering Genotype & phenotype Graft-versus-host reaction Immune clearance Immunological memory Immunoregulation Immunosurveillance IPEX syndrome lentiviral vector Lymphocytes Lymphocytes T Medical innovations Medical prognosis Memory cells Original Patients Peripheral blood regulatory T cells Ribonucleic acid RNA T cell receptors Transcription Xenografts |
title | Human‐engineered Treg‐like cells suppress FOXP3‐deficient T cells but preserve adaptive immune responses in vivo |
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