In vivo priming of T cells against cryptic determinants by dendritic cellsexposed to interleukin 6 and native antigen

T cells recognizing poorly displayed self determinants escape tolerance mec hanisms and persist in the adult repertoire. The process by which these T c ells are primed is not clear, but once activated, they can cause autoimmuni ty. Here, we show that dendritic cells treated with interleukin 6 (IL-6) pr ocess and present determinants from a model native antigen in a qualitative ly altered hierarchy, activating T cells in vitro and in vivo against deter minants that were previously cryptic because of poor display. IL-6 does not induce conventional maturation of dendritic cells but alters the pH of per ipheral, early endosomal compartments and renders the cells more susceptibl e to killing by chloroquine. Acidification of endosomes by ouabain mimics t he effect of IL-6 and allows processing of the same cryptic determinant. Th ese results suggest that cytokines such as IL-6 could initiate and help to propagate an autoimmune disease process by differentiating dendritic cells into a state distinct from that induced by normal maturation.