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.