Pathogenic conversion of Foxp3+ T cells into Th1 and Th17 cells in Stromal Keratitis

Ocular infection with herpes simplex virus 1 (HSV-1) can result in a chronic immuno-inflammatory lesion that is a significant cause of human blindness. IFN-γ producing CD4 + T cells are generally considered the main orchestrators, and lesions are more severe if the regulatory T cell (Treg) response is compromised. Tregs have been shown to lose FoxP3 (Treg lineage factor) and adopt alternate lineage fates in a changing cytokine environment. Moreover, little is known about the stability of Treg cells in an ongoing inflammatory reaction such as is the case of SK. In this study-using fate mapping mice, we were able to demonstrate that the population of ex-Tregs increased at the site of infection that is the cornea and also at the secondary lymphoid organs after HSV-1 infection. In vivo studies showed that these ex-Tregs acquired the Th1 and Th17 phenotype, which may play a destructive role in stromal keratitis. We also demonstrate in vivo that CD25lo subset of Tregs is less suppressive and more prone to conversion than CD25hi Tregs. Additionally, in-vitro studies suggested that Tregs in the presence of IL-12 converted into ex-Tregs, however this plasticity was prevented when Tregs were generated in the presence of DNMT inhibitor (Azacytidine). Thus, plasticity of Tregs might represent a problem during SK, which needs to be controlled with appropriate therapeutic procedures. Overall, our results indicate that Tregs lose FoxP3 expression in ocular inflammatory setting and drugs that reverse Treg plasticity could be useful to restore Treg function and to inhibit ocular immunopathology.