Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis.
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.
Wright
Graham P
GP
Department of Immunology, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom.
Notley
Clare A
CA
Xue
Shao-An
SA
Bendle
Gavin M
GM
Holler
Angelika
A
Schumacher
Ton N
TN
Ehrenstein
Michael R
MR
Stauss
Hans J
HJ
D019264:Adoptive Transfer; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000628:therapy*; D001324:Autoantigens / Q000276:immunology; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D012190:Retroviridae; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D001324:Autoantigens