Engineered MBP antigen-specific human regulatory T cells: direct and bystander immunosuppressive function (THER7P.954)

Clinical application of expanded T regulatory cells (Tregs) offers great promise for the treatment of undesirable immune responses. However, treatment with polyclonal Tregs, which are not specific, could potentially cause global immunosuppression. To avoid this problem, we propose that antigen-specific Tregs, based on chimeric antigen receptor (CAR) therapy in leukemia, would be desirable to control autoimmune responses. We engineered a myelin basic protein-specific TCR in a retroviral vector and transduced it to human naive CD4+ T cells and Tregs. The TCR V genes came from an MBP-specific T-cell clone derived from an MS patient (Ob2F3, Ota et al., Nature 346, 183-7, 1990). Transduced Tregs proliferated in vitro in response to MBP peptide on DR2 APC. Foxp3 and Helios expression were preserved in transduced Tregs during long-term expansion and these specific Tregs did not produce any inflammatory cytokines. Treg-unique activation markers, Foxp3 and LAP, were upregulated by MBP. Importantly, MBP-specific Tregs suppressed proliferation and cytokine production by MBP-specific T effector cells in the presence of MBP peptide. We also observed bystander suppression of MBP responses in vitro with Tregs specific for a different epitope when both peptides were present. We propose that MBP-specific Tregs can control pathologic inflammation as a future therapy in MS patients.