Control of alloreactivity using transient expression of a monoclonal antibody directed chimeric antigen receptor in conventional and regulatory T cells

Abstract

Abstract The genetic modification of T cells offers many promising cellular therapies, but little known about how the transient targeting of T cell or T cell subsets such as CD4+CD25+FoxP3+ regulatory cells (Treg) could be used to control alloreactivity. We used the expression of a chimeric antigen receptor that recognizes labeled therapeutic monoclonal antibodies, to control T cell activation in vivo. By specifying the location of activation of donor T cells during hematopoietic cell, we modulated graft-versus-host disease and anti-leukemia effects. We also controlled the activation of Treg cells which remain immunoregulatory. When recipient Treg are targeted to activate in response to MHC Class I mismatch, we observed significantly prolonged allogeneic islet graft survival in an antigen-specific manner, as secondary skin grafts were specifically protected against rejection. The transient genetic modification of T and Treg can have lasting effects on the immune system and could be used therapeutically to regulate alloreactivity.