B-Cell-Delivered Gene Therapy Induces Functional T Regulatory Cells and Leads to a Loss of Antigen-Specific Effector Cells

Skupsky, Jonathan; Ai-Hong Zhang; Yan Su; Scott, David W.
August 2010
Molecular Therapy;Aug2010, Vol. 18 Issue 8, p1527
Academic Journal
Previous reports have shown that B-cell-mediated gene therapy can induce tolerance in several animal models for autoimmune diseases and inhibitory antibody formation in hemophilia A mice. We know from our previous work that the induction of tolerance following B-cell therapy is dependent upon CD25+ regulatory T cells (Tregs). To extend these studies and identify the effects of this gene therapy protocol on the target CD4 T cells, we have adapted in vitro suppression assays using Tregs isolated from treated and control mice. Using carboxyfluorescein succinimidyl ester (CFSE) dilution as a measure of T-cell responsiveness to FVIII, we show that CD25+ Tregs from treated mice are more suppressive than those from control animals. To monitor the induction of antigen-specific Tregs, we repeated these studies in ovalbumin (OVA) peptide-specific DO11.10 T-cell receptor (TCR) transgenic mice. Tregs from DO11.10 mice treated with a tolerogenic OVA–Ig construct are better than polyclonal Tregs at suppressing the proliferation of responder cells stimulated with OVA peptide 323–339 (pOVA). Furthermore, we show that following B-cell therapy, there is an increase in antigen-specific FoxP3+ Tregs, and there is also a distinct decrease in antigen-specific CD4+ effector T cells. These changes in the lymphocyte population shift the balance away from effector function toward a tolerogenic phenotype.


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