Myricetin-induced oxidative stress suppresses murine T lymphocyte activation

A number of polyphenolic compounds present in fruits and vegetables have the capacity to modulate immune responses; however, the impact of the common plant-derived flavonoid myricetin on T lymphocyte function has not been investigated. We show that myricetin inhibited mouse T lymphocyte activation by bead-immobilized anti-CD3 and anti-CD28 monoclonal antibodies, as indicated by a dose-dependent reduction in cell proliferation and decreased synthesis of interferon-γ, interleukin (IL)-2, IL-4, and IL-17 associated with different T helper cell subsets. This effect was attributed to myricetin-induced reactive oxygen species (ROS) since myricetin caused hydrogen peroxide (H₂O₂) to accumulate in cell-free culture medium and H₂O₂ inhibited T cell proliferation and cytokine synthesis. In addition, the antioxidant N-acetyl cysteine restored the ability of myricetin-treated T lymphocytes to proliferate in response to a mitogenic stimulus. The presence of dendritic cells or bone marrow-derived macrophages negated the inhibitory effect of myricetin on T cell activation, and H₂O₂ in T cell cultures that were treated with exogenous H₂O₂ was reduced when antigen-presenting cells were also present. These findings suggest that antioxidant molecules produced by dendritic cells and macrophages protected T cells from myricetin-induced oxidative stress, and underscore the importance of considering immune cell interactions when evaluating the immunomodulatory activity of ROS-generating phytochemicals.