Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis

Wright, G P; Notley, C A; Xue, S A; Bendle, G M; Holler, A; Schumacher, T N; Ehrenstein, M R; Stauss, H J

Abstract

Regulatory T cells (Tregs) can suppress a wide range of immune cells, making them an ideal candidate for the treatment of autoimmunity. The potential clinical translation of targeted therapy with antigen-specific Tregs is hampered by the difficulties of isolating rare specificities from the natural polyclonal T cell repertoire. Moreover, the initiating antigen is often unknown in autoimmune disease. Here we tested the ability of antigen-specific Tregs generated by retroviral gene transfer to ameliorate arthritis through linked suppression and therefore without cognate recognition of the disease-initiating antigen. We explored two distinct strategies: T cell receptor (TCR) gene transfer into purified CD4+CD25+ T cells was used to redirect the specificity of naturally occurring Tregs; and co-transfer of FoxP3 and TCR genes served to convert conventional CD4+ T cells into antigen-specific regulators. Following adoptive transfer into recipient mice, the gene-modified T cells engrafted efficiently and retained TCR and FoxP3 expression. Using an established arthritis model, we demonstrate antigen-driven accumulation of the gene modified T cells at the site of joint inflammation, which resulted in a local reduction in the number of inflammatory Th17 cells and a significant decrease in arthritic bone destruction. Together, we describe a robust strategy to rapidly generate antigen-specific regulatory T cells capable of highly targeted inhibition of tissue damage in the absence of systemic immune suppression. This opens the possibility to target Tregs to tissue-specific antigens for the treatment of autoimmune tissue damage without the knowledge of the disease-causing autoantigens recognized by pathogenic T cells.

• Journal Article Type: Article
• Acceptance Date: Nov 10, 2009
• Online Publication Date: Nov 2, 2009
• Publication Date: Nov 10, 2009
• Deposit Date: Aug 1, 2016
• Journal: Proceedings of the National Academy of Sciences
• Electronic ISSN: 1091-6490
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 106
• Issue: 45
• Pages: 19078-19083
• DOI: https://doi.org/10.1073/pnas.0907396106
• Keywords: autoimmunity, gene therapy, T-cell receptor
• Public URL: http://researchrepository.napier.ac.uk/Output/320494