Impact of tissue resident memory T cells on the neuro-immunepathophysiology of anterior eye disease

摘要 T细胞是抗炎治疗前房角化诱导的持续性眼痛的主要临床靶点。 眼疾病，如干眼，但确定哪些T细胞亚群驱动前房的病理生理学， 眼病仍然是临床前研究的一个主题。新数据显示，相对而言， 发现了很少重新进入循环的T细胞的促炎亚群，它们在外周血中占主导地位。 人眼表面的，但在干眼病的临床前模型中几乎不存在。建立 这些组织驻留记忆T细胞（TRM）的眼睛需要病原体暴露或接种疫苗， 因为我们将实验室啮齿动物安置在非自然清洁的环境中， 病原体。由于缺乏免疫学经验，因此无法使用现存的啮齿动物模型来研究 TRM在前眼疾病的神经免疫机制中的影响，以及TRM与前眼疾病之间的潜在相互作用。 TRM和伤害感受器在眼部炎症和疼痛中的作用仍然是一个紧迫的知识空白。我们建议 通过用临床相关的眼部病原体感染小鼠以建立"人- 就像眼睛里的"TRM"，它可以被特异性地激活或耗尽。使用这个啮齿动物模型，我们将 调节前眼中TRM和/或伤害感受器的活性/存在，以检验中心假设， TRM和伤害感受器参与双向神经免疫相互作用，引起眼部疼痛， 炎症这些研究将获得关键的见解，神经免疫机制，驱动 前眼疾病的病理生理学，并显示如何事先病毒感染形状的表现， 随后的神经炎症。这项工作将为治疗眼部疼痛提供创新途径， 炎症，并通过首次对TRM的研究在神经免疫学领域产生广泛影响 与感觉神经系统的相互作用。

ABSTRACT T cells are major clinical targets for anti-inflammatory treatment of persistent ocular pain induced by anterior eye diseases such as dry eye, yet identification of which T cell subsets drive the pathophysiology of anterior eye disease remains a topic of intensive preclinical investigation. Emerging data shows that a relatively recently discovered pro-inflammatory subset of T cells that rarely re-enter circulation dominate the T cell niche on the ocular surface of humans, but are almost nonexistent in preclinical models of dry eye disease. Establishment of these tissue resident memory T cells (TRM) in the eye requires pathogen exposure or vaccination, and because we house laboratory rodents in unnaturally clean environments, they have extremely limited exposure to pathogens. This lack of immunologic experience has precluded the use of extant rodent models to investigate the impact of TRM in neuro-immune mechanisms of anterior eye disease, and the potential interaction between TRM and nociceptors in ocular inflammation and pain remains a pressing gap in knowledge. We propose to address this gap by infecting mice with a clinically relevant ocular pathogen to establish a population of “human- like” TRM in the eye that can be specifically targeted for activation or depletion. Using this rodent model, we will modulate the activity/presence of TRM and/or nociceptors in the anterior eye to test the central hypothesis that TRM and nociceptors engage in bidirectional neuro-immune interactions that cause ocular pain and inflammation. These studies will gain critical insights into neuro-immune mechanisms that drive the pathophysiology of anterior eye disease, and show how prior viral infection shapes the manifestation of subsequent neuro-inflammation. This work will inform innovative avenues for the treatment of ocular pain and inflammation, and bear broad impact in the field of neuro-immunology through a first-ever investigation of TRM interactions with the sensory nervous system.