Mechanisms of CD4+ T tolerance to a corneal epithelial neoantigen.

Tissue-specific peripheral tolerance mechanisms are essential to prevent autoimmunity. The cornea is immune privileged, and anterior chamber-associated immune deviation (ACAID) governs its inner surface. However, the mechanisms governing corneal epithelial (outer surface) antigens remain unknown. Using an inducible, cornea-restricted neoantigen mouse model, we found that tolerance of corneal epithelial antigens is associated with antigen-specific regulatory T cell (Treg) induction. Although the cornea is both avascular and alymphatic, its epithelial antigens are still efficiently presented by ocular surface-derived antigen-presenting cells to T cells in draining lymph nodes under homeostatic conditions, leading to conventional antigen-specific Treg expansion without ocular pathology. This tolerance was not absolute: systemic immunization redirected antigen-specific responses toward pathogenic effector T cells that disrupted epithelial barrier function. These findings identify Treg induction and anergy as mechanisms linked to corneal epithelial immune homeostasis and demonstrate that inflammatory priming can render a previously tolerated corneal antigen into an autoimmune target, providing mechanistic insight into ocular surface disease pathogenesis.