Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses

• Published in: Blood Vol. 125; no. 7; pp. 1107 - 1115
• Main Authors: Kim, Yong Chan, Zhang, Ai-Hong, Su, Yan, Rieder, Sadiye Amcaoglu, Rossi, Robert J., Ettinger, Ruth A., Pratt, Kathleen P., Shevach, Ethan M., Scott, David W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2015; American Society of Hematology
• Subjects: Adult; Aged; Animals; B-Lymphocytes, Regulatory - immunology; B-Lymphocytes, Regulatory - metabolism; Cell Engineering - methods; Cells, Cultured; Factor VIII - genetics; Factor VIII - immunology; Factor VIII - metabolism; Genetic Engineering; Genetic Therapy; Hemophilia A - genetics; Hemophilia A - immunology; Humans; Immune Tolerance - genetics; Immunobiology; Male; Mice; Middle Aged; T-Cell Antigen Receptor Specificity - genetics; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2014-04-566786

Expansion of human regulatory T cells (Tregs) for clinical applications offers great promise for the treatment of undesirable immune responses in autoimmunity, transplantation, allergy, and antidrug antibody responses, including inhibitor responses in hemophilia A patients. However, polyclonal Tregs are nonspecific and therefore could potentially cause global immunosuppression. To avoid this undesirable outcome, the generation of antigen-specific Tregs would be advantageous. Herein, we report the production and properties of engineered antigen-specific Tregs, created by transduction of a recombinant T-cell receptor obtained from a hemophilia A subject's T-cell clone, into expanded human FoxP3+ Tregs. Such engineered factor VIII (FVIII)-specific Tregs efficiently suppressed the proliferation and cytokine production of FVIII-specific T-effector cells. Moreover, studies with an HLA-transgenic, FVIII-deficient mouse model demonstrated that antibody production from FVIII-primed spleen cells in vitro were profoundly inhibited in the presence of these FVIII-specific Tregs, suggesting potential utility to treat anti-FVIII inhibitory antibody formation in hemophilia A patients. •Generation and function of specific human Tregs.•Specific regulation of FVIII responses by engineered human Tregs.