Engineered myelin basic protein (MBP)-specific human T regulatory cells ameliorate myelin oligodendrocyte glycoprotein (MOG) peptide-induced Experimental Autoimmune Encephalomyelitis in vivo

Abstract

Abstract Application of expanded polyclonal T regulatory cells (Tregs) offers great promise for the treatment of undesirable immune responses. To increase efficacy and reduce possible non-specific side effects, we elected to create antigen-specific Tregs, based on chimeric antigen receptor (CAR) therapy in leukemia. Therefore, we have engineered a myelin basic protein-specific TCR in a retroviral vector and transduced it to human naïve CD4+ T cells and Tregs. The TCR V genes came from an MBP-specific T-cell clone derived from an MS patient [1–3](Ob2F3). We observed that transduced Tregs were activated in vitro in response to MBP peptide on DR15 APC and upregulated Foxp3, LAP and Helios expression. As expected, these engineered MBP-specific Tregs suppressed proliferation and cytokine production by MBP-specific T effector cells in the presence of MBP peptide. Mechanistic studies demonstrated that suppression may involve transfer of soluble mediators but is enhanced by cell contact. Furthermore, transfer of human MBP-specific Tregs into MOG-immunized mice was able to ameliorate EAE in HLA DR15-transgenic mice. MBP-specific Tregs migrated into CNS in greater numbers than irrelevant FVIII-specific Tregs in day 2 after infusion, and H&E staining indicated that infusion of MBP-specific Tregs prevented perivascular inflammatory infiltration in CNS. Thus, we propose that engineered MBP-specific Tregs may be able to control pathologic inflammation in MS in vivo.