Thiol-mediated redox modulation of the adaptive immune response

THIOL-MEDIATED REDOX MODULATION OF THE ADAPTIVE IMMUNE RESPONSE By Zhonghua Yan Chair: Ruma Banerjee T cell activation and proliferation requires a reducing microenvironment that is provided by antigen presenting cells especially dendritic cells (DCs). Naturally occurring CD4CD25Foxp3 regulatory T cells (Tregs) suppress proliferation of CD4CD25 effector T cells (Teffs) by mechanisms that are not well understood. Here, we have demonstrated that inhibition by Tregs of DC-induced extracellular redox remodeling is a component of the Treg immunosuppressive mechanism. We showed that the mechanism of redox remodeling during T cell activation involved secretion of glutathione (GSH) by dendritic cells and its subsequent cleavage to cysteine. Extracellular cysteine accumulation resulted in a lower redox potential, which is conducive to proliferation, and changed the net redox status of exofacial protein domains. Suppression of DC-dependent Teff cell proliferation by Tregs was correlated with a significant diminution in extracellular cysteine concentration and was abrogated by addition of exogenous cysteine. We demonstrated that Treg-mediated redox perturbation was antigen-dependent, antigen-