CD8 Regulates T Regulatory Cell Production of IL-6 and Maintains Their Suppressive Phenotype in Allergic Lung Disease

Abstract

Naturally occurring CD4+CD25+Foxp3+ T regulatory cells (nTregs) regulate lung allergic responses through production of IL-10 and TGF-β. nTregs from CD8−/− mice failed to suppress lung allergic responses and were characterized by reduced levels of Foxp3, IL-10, and TGF-β, and high levels of IL-6. Administration of anti–IL-6 or anti–IL-6R to wild-type recipients prior to transfer of CD8−/− nTregs restored suppression. nTregs from IL-6−/− mice were suppressive, but lost this capability if incubated with IL-6 prior to transfer. The importance of CD8 in regulating the production of IL-6 in nTregs was demonstrated by the loss of suppression and increases in IL-6 following transfer of nTregs from wild-type donors depleted of CD8+ cells. Transfer of nTregs from CD8−/− donors reconstituted with CD8+ T cells was suppressive, and accordingly, IL-6 levels were reduced. These data identify the critical role of CD8–T regulatory cell interactions in regulating the suppressive phenotype of nTregs through control of IL-6 production.