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-beta. Interestingly, we demonstrated that MPA inhibited the LPS-induced synthesis of tumor necrosis factor-alpha, IL-12, and interferon-gamma (IFN-gamma) in DCs. Importantly, we found that adding exogenous IFN-gamma to MPA restored both the synthesis of cytokines and the ability to activate CD8(+) T cells. However, adding IL-12 or tumor necrosis factor-alpha had no effect. These results suggest that IFN-gamma has an important role in licensing DCs to prime CD4-independent CD8 allogeneic T cells via an autocrine loop. (Blood.2010;116(16):3089-3098)