A combination of cyclophosphamide and interleukin-2 allows CD4+ T cells converted to Tregs to control scurfy syndrome

• Published in: Blood Vol. 137; no. 17; pp. 2326 - 2336
• Main Authors: Delville, Marianne, Bellier, Florence, Leon, Juliette, Klifa, Roman, Lizot, Sabrina, Vinçon, Hélène, Sobrino, Steicy, Thouenon, Romane, Marchal, Armance, Garrigue, Alexandrine, Olivré, Juliette, Charbonnier, Soëli, Lagresle-Peyrou, Chantal, Amendola, Mario, Schambach, Axel, Gross, David, Lamarthée, Baptiste, Benoist, Christophe, Zuber, Julien, André, Isabelle, Cavazzana, Marina, Six, Emmanuelle
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.04.2021; American Society of Hematology
• Subjects: Biotechnology; Cellular Biology; Gene Therapy; Hematology; Human health and pathology; Life Sciences
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2020009187

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by mutations in forkhead box P3 (FOXP3), which lead to the loss of function of regulatory T cells (Tregs) and the development of autoimmune manifestations early in life. The selective induction of a Treg program in autologous CD4+ T cells by FOXP3 gene transfer is a promising approach for curing IPEX. We have established a novel in vivo assay of Treg functionality, based on adoptive transfer of these cells into scurfy mice (an animal model of IPEX) and a combination of cyclophosphamide (Cy) conditioning and interleukin-2 (IL-2) treatment. This model highlighted the possibility of rescuing scurfy disease after the latter's onset. By using this in vivo model and an optimized lentiviral vector expressing human Foxp3 and, as a reporter, a truncated form of the low-affinity nerve growth factor receptor (ΔLNGFR), we demonstrated that the adoptive transfer of FOXP3-transduced scurfy CD4+ T cells enabled the long-term rescue of scurfy autoimmune disease. The efficiency was similar to that seen with wild-type Tregs. After in vivo expansion, the converted CD4FOXP3 cells recapitulated the transcriptomic core signature for Tregs. These findings demonstrate that FOXP3 expression converts CD4+ T cells into functional Tregs capable of controlling severe autoimmune disease. •The combination of Cy conditioning and IL-2 allows suppressive T cells to rescue scurfy mice after disease onset.•Transcriptomic analysis reveals a lasting restoration of Treg identity in FOXP3-transduced scurfy cells, even in an inflammatory environment. [Display omitted]