γδ T Cell–Dependent Regulatory T Cells Prevent the Development of Autoimmune Keratitis

Abstract

To prevent potentially damaging inflammatory responses, the eye actively promotes local immune tolerance via a variety of mechanisms. Owing to trauma, infection, or other ongoing autoimmunity, these mechanisms sometimes fail, and an autoimmune disorder may develop in the eye. In mice of the C57BL/10 (B10) background, autoimmune keratitis often develops spontaneously, particularly in the females. Its incidence is greatly elevated in the absence of γδ T cells, such that ∼80% of female B10.TCRδ−/− mice develop keratitis by 18 wk of age. In this article, we show that CD8+ αβ T cells are the drivers of this disease, because adoptive transfer of CD8+, but not CD4+, T cells to keratitis-resistant B10.TCRβ/δ−/− hosts induced a high incidence of keratitis. This finding was unexpected because in other autoimmune diseases, more often CD4+ αβ T cells, or both CD4+ and CD8+ αβ T cells, mediate the disease. Compared with wild-type B10 mice, B10.TCRδ−/− mice also show increased percentages of peripheral memory phenotype CD8+ αβ T cells, along with an elevated frequency of CD8+ αβ T cells biased to produce inflammatory cytokines. In addition, B10.TCRδ−/- mice have fewer peripheral CD4+ CD25+ Foxp3+ αβ regulatory T cells (Tregs), which express lower levels of receptors needed for Treg development and function. Together, these observations suggest that in B10 background mice, γδ T cells are required to generate adequate numbers of CD4+ CD25+ Foxp3+ Tregs, and that in B10.TCRδ−/− mice a Treg deficiency allows dysregulated effector or memory CD8+ αβ T cells to infiltrate the cornea and provoke an autoimmune attack.