IL-10 and Natural Regulatory T Cells: Two Independent Anti-Inflammatory Mechanisms in Herpes Simplex Virus-Induced Ocular Immunopathology

Abstract

Two prominent anti-inflammatory mechanisms involved in controlling HSV-1-induced corneal immunopathology (stromal keratitis or SK) are the production of the cytokine IL-10 and the activity of natural regulatory T cells (nTregs). It is not known whether, under in vivo conditions, IL-10 and nTregs influence the corneal pathology independently or in concert. In the current study using wild-type and IL-10−/− animals, we have assessed the activity of nTregs in the absence of IL-10 both under in vitro and in vivo conditions. The IL-10−/− animals depleted of nTregs before ocular infection showed more severe SK lesions as compared with the undepleted IL-10−/− animals. In addition, nTregs purified from naive WT and IL-10−/− animals were equally able to suppress the proliferation and the cytokine production from anti-CD3-stimulated CD4+CD25− T cells in vitro. Furthermore, intracellular cytokine staining results indicated that nonregulatory cells expressing B220 and CD25 markers were the major IL-10-producing cell types in the lymphoid tissues of HSV-infected mice. In contrast, in the infected corneas, cells with the CD11b+Gr1+ phenotype along with a minor population of Foxp3−CD4+ and a few F4/80+ cells produced IL-10. Our current investigations indicate that at least two independent anti-inflammatory mechanisms are involved in limiting the corneal lesions in SK, both of which may need to be modulated to control SK therapeutically.