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CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII

Regulatory T cells (Tregs) control immune responses in autoimmune disease, transplantation, and enable antigen-specific tolerance induction in protein-replacement therapies. Tregs can exert a broad array of suppressive functions through their T cell receptor (TCR) in a tissue-directed and antigen-sp...

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Autores principales: Rana, Jyoti, Perry, Daniel J., Kumar, Sandeep R.P., Muñoz-Melero, Maite, Saboungi, Rania, Brusko, Todd M., Biswas, Moanaro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417451/
https://www.ncbi.nlm.nih.gov/pubmed/33940160
http://dx.doi.org/10.1016/j.ymthe.2021.04.034
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author Rana, Jyoti
Perry, Daniel J.
Kumar, Sandeep R.P.
Muñoz-Melero, Maite
Saboungi, Rania
Brusko, Todd M.
Biswas, Moanaro
author_facet Rana, Jyoti
Perry, Daniel J.
Kumar, Sandeep R.P.
Muñoz-Melero, Maite
Saboungi, Rania
Brusko, Todd M.
Biswas, Moanaro
author_sort Rana, Jyoti
collection PubMed
description Regulatory T cells (Tregs) control immune responses in autoimmune disease, transplantation, and enable antigen-specific tolerance induction in protein-replacement therapies. Tregs can exert a broad array of suppressive functions through their T cell receptor (TCR) in a tissue-directed and antigen-specific manner. This capacity can now be harnessed for tolerance induction by “redirecting” polyclonal Tregs to overcome low inherent precursor frequencies and simultaneously augment suppressive functions. With the use of hemophilia A as a model, we sought to engineer antigen-specific Tregs to suppress antibody formation against the soluble therapeutic protein factor (F)VIII in a major histocompatibility complex (MHC)-independent fashion. Surprisingly, high-affinity chimeric antigen receptor (CAR)-Treg engagement induced a robust effector phenotype that was distinct from the activation signature observed for endogenous thymic Tregs, which resulted in the loss of suppressive activity. Targeted mutations in the CD3ζ or CD28 signaling motifs or interleukin (IL)-10 overexpression were not sufficient to restore tolerance. In contrast, complexing TCR-based signaling with single-chain variable fragment (scFv) recognition to generate TCR fusion construct (TRuC)-Tregs delivered controlled antigen-specific signaling via engagement of the entire TCR complex, thereby directing functional suppression of the FVIII-specific antibody response. These data suggest that cellular therapies employing engineered receptor Tregs will require regulation of activation thresholds to maintain optimal suppressive function.
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spelling pubmed-84174512022-09-01 CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII Rana, Jyoti Perry, Daniel J. Kumar, Sandeep R.P. Muñoz-Melero, Maite Saboungi, Rania Brusko, Todd M. Biswas, Moanaro Mol Ther Original Article Regulatory T cells (Tregs) control immune responses in autoimmune disease, transplantation, and enable antigen-specific tolerance induction in protein-replacement therapies. Tregs can exert a broad array of suppressive functions through their T cell receptor (TCR) in a tissue-directed and antigen-specific manner. This capacity can now be harnessed for tolerance induction by “redirecting” polyclonal Tregs to overcome low inherent precursor frequencies and simultaneously augment suppressive functions. With the use of hemophilia A as a model, we sought to engineer antigen-specific Tregs to suppress antibody formation against the soluble therapeutic protein factor (F)VIII in a major histocompatibility complex (MHC)-independent fashion. Surprisingly, high-affinity chimeric antigen receptor (CAR)-Treg engagement induced a robust effector phenotype that was distinct from the activation signature observed for endogenous thymic Tregs, which resulted in the loss of suppressive activity. Targeted mutations in the CD3ζ or CD28 signaling motifs or interleukin (IL)-10 overexpression were not sufficient to restore tolerance. In contrast, complexing TCR-based signaling with single-chain variable fragment (scFv) recognition to generate TCR fusion construct (TRuC)-Tregs delivered controlled antigen-specific signaling via engagement of the entire TCR complex, thereby directing functional suppression of the FVIII-specific antibody response. These data suggest that cellular therapies employing engineered receptor Tregs will require regulation of activation thresholds to maintain optimal suppressive function. American Society of Gene & Cell Therapy 2021-09-01 2021-05-01 /pmc/articles/PMC8417451/ /pubmed/33940160 http://dx.doi.org/10.1016/j.ymthe.2021.04.034 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Rana, Jyoti
Perry, Daniel J.
Kumar, Sandeep R.P.
Muñoz-Melero, Maite
Saboungi, Rania
Brusko, Todd M.
Biswas, Moanaro
CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII
title CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII
title_full CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII
title_fullStr CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII
title_full_unstemmed CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII
title_short CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII
title_sort car- and truc-redirected regulatory t cells differ in capacity to control adaptive immunity to fviii
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417451/
https://www.ncbi.nlm.nih.gov/pubmed/33940160
http://dx.doi.org/10.1016/j.ymthe.2021.04.034
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