Using transgenic expression of a MHC Class II/peptide restricted T cell receptor in mature CD8+ T cells to target auto-antigen decorated antigen presenting cells for destruction

Abstract

Abstract CD4+ T cells are thought to be necessary for MS neuroinflammation, coordinating the destructive immune response following recognition of central nervous system (CNS) antigens in the context of MHC class II molecules on professional antigen presenting cells (APC). Recognition of CNS antigens within the CNS is required to drive CD4 re-activation and subsequent production of cytokines and chemokines crucial to the recruitment of secondary immune effector cells. This CD4+ T cell driven recruitment in turn results in induction of immune pathology while also priming APC to enhance future T cell-APC interactions. Recent studies in cancer immunotherapy have defined protocols for inducing expression of chimeric antigen-specific T cell receptors (CAR) in mature CD8 T cells for the purpose of inducing destruction of antigen bearing cells, apparently without modulating the underlying effector profile of the transduced T cell (i.e., CD8 cells are still cytotoxic through perforin and granzymes). Here we detail the use of defined MHC class II/peptide restricted T cell receptor expression in mature CD8 T cells in an effort to target for destruction MHC class II expressing professional antigen presenting cells containing CNS antigen while sparing MHC II negative neurons and oligodendrocytes. Crucially, an effective antigen elimination strategy would not only modulate the cognate antigen recognized by the transgenic TCR but, given the propensity of APC to present multiple antigens derived from the same phagocytized material, should also impact uncharacterized CNS antigen epitopes. This study examines a novel potential therapeutic modality for its efficacy in neuroinflammation. Supported by NMSS pilot grant PP3361.