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

视神经脊髓炎(NMO)是一种以水通道蛋白水通道蛋白-4(AQP4)为靶抗原的中枢神经系统(CNS)自身免疫性疾病。在这里，我们已经确定了AQP4的免疫优势MHC II类(I-Ab)限制性表位，并开发了一种四聚体，允许在正常谱系中对AQP4(201-220)特异性T细胞进行计数和表型鉴定。在本提案的第一部分中，我们将重点介绍负责形成AQP4特异性T细胞库的抗原提呈细胞(APC)。在该项目的第二部分，在成熟的AQP4特异性曲库中，我们将分析AQP4特异性T细胞在外周免疫间隔中的启动部位的决定因素，这可能指导传统的AQP4特异性T细胞与Tfh细胞的承诺，而不是直接导致中枢神经系统免疫病理的效应性T细胞。该项目的结果可能为NMO中抗原特异性治疗干预的发展奠定基础。

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.