Regulatory T cells and immune tolerance to coagulation factor IX in the context of intramuscular AAV1 gene transfer.
Regulatory T cells play a major role in induction and maintenance of immune tolerance and immunological homeostasis. A variety of strategies have been attempted to induce regulatory T cells for control of unwanted, adverse immunity in autoimmune diseases, transplantation as well as gene transfer. We recently reported efficient induction of immune tolerance to coagulation factor IX (FIX) following intramuscular AAV1 gene transfer. In the current study, we performed a systematic and comprehensive examination of the role and function of regulatory T cells in induction and maintenance of FIX tolerance in the context of intramuscular AAV1 gene transfer. We observed no significant upregulation of regulatory T cells in the FIX-tolerant mice. In addition, adoptive transfer of splenocytes from FIX-tolerant mice did not suppress anti-hFIX immunity in recipient mice. Both in vitro and in vivo depletion of regulatory T cells failed to reverse FIX tolerance. These observations revealed that regulatory T cells do not play a significant role in the maintenance/protection of the established FIX tolerance. Our results provide critical insight into the role and function of regulatory T cells in induction and maintenance/protection of immune tolerance in gene transfer, complementing the current paradigm of immune tolerance mechanism.
Kelly
Meagan
M
Division of Hematology/Oncology, Cancer Institute, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
Bharadwaj
Arpita S
AS
Tacke
Frank
F
Chao
Hengjun
H
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005164:Factor IX / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D005164:Factor IX