Interferon gamma licensing of human dendritic cells in T-helper–independent CD8+ alloimmunity

The high frequency of allogeneic reactive CD8+ T cells in human and their resistance to immunosuppression might be one of the reasons why successful tolerance-inducing strategies in rodents have failed in primates. Studies on the requirement for T-helper cells in priming CD8+ T-cell responses have led to disparate findings. Recent studies have reported CD8+-mediated allograft rejection independently of T-helper cells; however, the mechanisms that govern the activation of these T cells are far from being elucidated. In this study, we demonstrated that lipopolysaccharide-treated dendritic cells (DCs) were able to induce proliferation and cytotoxic activity of allogeneic CD8+ T cells independently of CD4+ T cells, while adding mycophenolic acid (MPA) to LPS abolished this capacity and resulted in anergic CD8+ T cells that secreted high levels of interleukin-4 (IL-4), IL-5, IL-10, and transforming growth factor-β. Interestingly, we demonstrated that MPA inhibited the LPS-induced synthesis of tumor necrosis factor-α, IL-12, and interferon-γ (IFN-γ) in DCs. Importantly, we found that adding exogenous IFN-γ to MPA restored both the synthesis of cytokines and the ability to activate CD8+ T cells. However, adding IL-12 or tumor necrosis factor-α had no effect. These results suggest that IFN-γ has an important role in licensing DCs to prime CD4-independent CD8 allogeneic T cells via an autocrine loop.