There is an unmet need for effectively treating dry eye disease (DED), a T cell-mediated chronic, inflammatory ocular surface disorder. Given the potential of nonneuronal adrenergic system in modulating T cell response, we herein investigated the therapeutic efficacy and the underlying mechanisms of a specific alpha 2 adrenergic receptor agonist (AGN-762, selective for α2B/2C receptor subtypes) in a mouse model of DED. Experimental DED was treated with the AGN-762 by oral gavage, either at disease induction or after disease establishment, and showed sustained amelioration, along with reduced expression of DED-pathogenic cytokines in ocular surface tissues, decreased corneal MHC-II