Redox remodeling as an immunoregulatory strategy

Activation and proliferation of T cells require a reducing extracellular microenvironment in the immune synapse that is provided by antigen presenting cells, especially dendritic cells. Stimulation of dendritic cells by T cells activates the NF-kappaB pathway in dendritic cells and induces an antioxidant response. It also enhances system x(c)(-)-dependent cystine uptake, leading to enhanced glutathione synthesis, export, and, finally, degradation to cysteine outside the cell. Accumulation of extracellular cysteine supports glutathione synthesis in T cells while also leading to a more reducing redox potential that is needed for T cell proliferation. Naturally occurring regulatory T cells, a suppressor subpopulation of T cells, prevent autoimmune diseases and maintain peripheral tolerance by suppressing self-reactive effector T cells. They also suppress beneficial immune responses to parasites, viruses, and tumors. However, their mechanism of suppression is still not fully understood. Recently, we have found that inhibition by regulatory T cells of dendritic cell-induced extracellular redox remodeling is a component of the regulatory T cell suppression mechanism. In this review, we describe recent advances in our understanding of redox regulation and signaling in the adaptive immune system with a focus on T cell activation by dendritic cells. The role of regulatory T cells in perturbing redox remodeling by dendritic cells and its implications as a general regulatory T cell suppression mechanism are discussed.