Development and functional specialization of Aquaporin-4-specific T-cells in a disease model of neuromyelitis optica (B06)

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Neuromyelitis optica (NMO) is a debilitating autoimmune disease of the central nervous system (CNS), in which the target autoantigen is the water channel protein Aquaporin-4 (AQP4). Here, we have identified the immunodominant MHC class II (I-Ab) restricted epitope of AQP4 and developed a tetramer that allowed the enumeration and phenotypic characterization of AQP4(201-220)-specific T cells in the normal repertoire. In the first section of this proposal, we will focus on the antigen presenting cell (APC) compartment that is responsible for the shaping of the AQP4-specific T cell repertoire. In the second part of the project, in the mature AQP4-specific repertoire, we will analyze determinants of the priming site of AQP4-specific T cells in the peripheral immune compartment that might guide the commitment of conventional AQP4-specific T cells to Tfh cells vs effector T cells that directly cause immunopathology in the CNS. The results of this project may lay the foundation for the development of antigen-specific therapeutic interventions in NMO.