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

摘要 T细胞是前眼持续性眼痛抗炎治疗的主要临床靶点 干眼等疾病，但尚未确定哪些T细胞亚群推动了前眼的病理生理 疾病仍然是密集的临床前研究的主题。新兴数据显示，相对最近的一次 发现的致炎T细胞亚群很少重新进入循环，它们主导着T细胞在 在干眼病的临床前模型中几乎不存在。设立 眼睛中的这些组织驻留记忆T细胞(TRM)需要接触病原体或接种疫苗，而且因为 我们将实验室啮齿动物安置在非自然清洁的环境中，它们接触的环境极其有限。 病原体。由于缺乏免疫学经验，无法使用现有的啮齿动物模型来研究 TRM在前部眼病神经免疫机制中的作用及其相互作用 眼部炎症和疼痛中的伤害性感受器仍然是一个紧迫的知识缺口。我们建议解决以下问题 通过用一种临床相关的眼部病原体感染小鼠来建立一个类似于人类的TRM种群，从而产生这个缺口 在眼睛里，可以特别针对激活或耗尽。使用这个啮齿动物模型，我们将调制 前眼TRM和/或伤害性感受器的活动/存在，以检验TRM和/或伤害性感受器的中枢假设 伤害性感受器参与双向神经免疫相互作用，导致眼睛疼痛和炎症。 此外，这些动物将被用于干眼病的干燥应激模型，包括干眼症和干眼病。 消耗驻留(TRM)和/或循环中的病毒特异性CD8+记忆T细胞，以确定相对 这些经验依赖的记忆免疫细胞群对干眼症病理生理学的影响。这些 研究将获得对驱动前眼病理生理的神经免疫机制的关键见解 并确定先前的病毒感染如何塑造随后的神经性炎症的表现。 这项工作将为治疗人类眼部疼痛和炎症提供创新的途径，并具有广泛的意义 首次研究TRM与感觉的相互作用对神经免疫学领域的影响 神经系统。

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 interactions 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. Additionally, these animals will be used in a desiccating stress model of dry eye disease with and without depletion of resident (TRM), and/or circulating virus-specific CD8+ memory T cells, to determine the relative impact of these experience-dependent memory immune cell populations on dry eye pathophysiology. These studies will gain critical insights into neuro-immune mechanisms that drive the pathophysiology of anterior eye disease and determine how prior viral infection shapes the manifestation of subsequent neuro-inflammation. This work will inform innovative avenues for the treatment of human ocular pain and inflammation and bear broad impact for the field of neuro-immunology through first-ever investigation of TRM interactions with the sensory nervous system.