Reactive Oxygen Species Regulate T Cell Immune Response in the Tumor Microenvironment

Figure 2

Multifaceted regulation of T cell responses by ROS. CD3 activation leads to rapid influx of calcium promoting ROS production. However, the connection between calcium and ROS production is under debate. Both signals are essential for TCR signaling. ROS trigger activation-induced cell death of T cells via Fas/FasL pathway. The low levels of mitochondrial ROS are required for T cell proliferation, while high levels of ROS inhibit NFAT5 by binding to IL-6 promoter and decrease T cell proliferation. Mitochondrial ROS are indispensable for T cell activation by regulating IL-2 and IL-4 secretion. Chronic exposure to ROS may inhibit NF-κB phosphorylation and activation, which induces T lymphocytes hyporesponsiveness. NOX-2 derived ROS increase IFN-γ production via increasing the levels of JNK and NF-κB phosphorylation, transcription factors STAT-1 and T-bet, and cytokines secretion of IL-2, IL-4, TNF-α, and GM-CSF. Further, NOX-2 derived ROS decrease phosphorylation of STAT3 and production of IL-10, TGF-β, and IL-17. Mitochondrial ROS regulate differentiation of Th17 cells and Th1 cells. Low levels of ROS induce the immunoregulatory enzyme, indoleamine 2,3-dioxygenase, and enhance the function of Tregs. NOX/ROS is a key upstream component of CD3 and CD28 signaling pathways during Tc1 cell development.