Exhaustion of Human Dendritic Cells Results in a Switch from the IL-15R/IL-15- to IL-2R/IL-2-driven Expansion of Antigen-specific CD8+ T Cells

Abstract

Abstract Maturation of dendritic cell (DC) is considered to be crucial for their ability to promote clonal expansion of antigen-specific T cells. Here, we show that the ability to expand human antigen-specific CD8+ T cells is a feature of specialized “effector” DCs at early stages of maturation, and it is suppressed in “exhausted” DCs at late stages of maturation and in DCs matured in the conditions of chronic inflammation. Effector DCs, at early stages of maturation induced by TLR ligands and interferons, express membrane IL-15Rα/IL-15 complex, which promotes highly efficient and IL-2/IL-2Rα-independent expansion of MART-1-specific IL-15Rαhigh CD8+ T cells and cooperates with DC-produced IL-12p70 in inducing poly-functional CTL phenotype. In sharp contrast, exhausted DCs which lack membrane IL-15Rα/IL-15 complex, utilize a significantly less efficient IL-2Rα/IL-2 trans-presentation pathway to co-stimulate CD8+ T cells. The currently-reported switch from the IL-15Rα/IL-15- to IL-2Rα/IL-2 costimulatory pathway in exhausted DCs helps to understand the role of inflammation in clonal expansion and contraction of CD8+ T cells at different stages of immune responses and helps to design improved modes of immunotherapy of cancer and chronic infections.