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Forced Fox-P3 expression can improve the safety and antigen-specific function of engineered regulatory T cells

McGovern, J; Holler, A; Thomas, S; Stauss, HJ; (2022) Forced Fox-P3 expression can improve the safety and antigen-specific function of engineered regulatory T cells. Journal of Autoimmunity , 132 , Article 102888. 10.1016/j.jaut.2022.102888. Green open access

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Abstract

Regulatory T cells (Treg) are potent inhibitors of autoreactive T cells. The intracellular transcription factor FoxP3 controls the expression levels of a diverse set of genes and plays a critical role in programming functional Tregs. Although, antigen-specific Tregs are more potent than polyclonal Tregs in treating ongoing autoimmunity, phenotype plasticity associated with loss of FoxP3 expression in Tregs can lead to the conversion into antigen-specific effector T cells which might exacerbate autoimmune pathology. In this study, we designed a retroviral vector driving the expression of FoxP3 and a human HLA-DR-restricted TCR from the same promoter. Transduction of purified human Tregs revealed that all TCR-positive cells had elevated levels of FoxP3 expression, increased CD25 and CTLA4 expression and potent suppressive function. Elevated FoxP3 expression did not impair the in vitro expansion of engineered Tregs. Adoptive transfer into HLA-DR transgenic mice revealed that FoxP3+TCR engineered Tregs showed long-term persistence with stable FoxP3 and TCR expression. In contrast, adoptive transfer of Tregs engineered with TCR only resulted in the accumulation of TCR-positive, FoxP3-negative T cells which displayed antigen-specific effector function when stimulated with the TCR-recognised peptides. Our data indicate that forced expression of FoxP3 can prevent accumulation of antigen-specific effector T cells without impairing the engraftment and persistence of engineered Tregs.

Type: Article
Title: Forced Fox-P3 expression can improve the safety and antigen-specific function of engineered regulatory T cells
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jaut.2022.102888
Publisher version: https://doi.org/10.1016/j.jaut.2022.102888
Language: English
Additional information: © 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10155242
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