Lymphocytic infiltration of the lacrimal gland and ocular surface in autoimmune diseases such as Sjögren's syndrome (SS) causes an aqueous-deficient dry eye that is associated with significant morbidity. Previous studies from our laboratory and others have established autoimmune regulator (Aire)–deficient mice as a useful model to examine exocrinopathy and ocular surface disease associated with SS. Consistent with human SS, autoreactive CD4⁺ T cells play an indispensible role in the development of exocrine and ocular surface disease in Aire knockout mice. We report that in addition to CD4⁺ T cells, a large number of macrophages infiltrate the corneal stroma, limbus, and lacrimal glands of diseased mice. Adoptive transfer of autoreactive CD4⁺ T cells from Aire knockout mice led to local infiltration of macrophages and ocular surface damage in immunodeficient recipients. Depletion of local macrophages, through subconjunctival injection of clodronate liposome, attenuated lissamine green staining and improved ocular phenotype. Alternatively, systemic depletion of macrophages had no effect on ocular phenotype but led to significant improvements in lacrimal gland exocrinopathy and tear secretion. Our results suggested that autoreactive CD4⁺ T cells provoked macrophage infiltration to the eye and lacrimal gland, where they played a functional role in directing the development of autoimmune dry eye.