OX40–OX40 Ligand Interaction in T-Cell-Mediated Immunity and Immunopathology

T-cell activation is mediated not only by antigen stimulation through T-cell receptors but also by costimulatory signals through costimulatory molecules. Among several costimulatory molecules, the tumor necrosis factor (TNF) receptor family member OX40 plays a key role in the survival and homeostasis of effector and memory T cells. According to the conventional understanding of OX40 costimulation, an interaction between OX40 and OX40 ligand (OX40L) occurs when activated T cells bind to professional antigen-presenting cells (APCs). The T-cell functions, including cytokine production, expansion, and survival, are then enhanced by the OX40 costimulatory signals. Over the last half-decade, evidence has accumulated that OX40 signals are critical for controlling the function and differentiation of Foxp3+ regulatory T cells, indicating a new aspect of OX40-mediated autoimmunity. Furthermore, the expression of OX40L by mast cells was shown to be important for controlling inflammation through regulatory T-cell function. Besides the essential role played by OX40 signaling in generating memory CD4 T cells, recent reports show that it also has a unique role in generating memory CD8 T cells. In addition, recent genome-wide association studies have identified single-nucleotide polymorphisms of the OX40L and OX40 genes that are related to cardiovascular diseases and SLE, providing direct evidence for the involvement of the OX40–OX40L interaction in human diseases. Here, we review recent progress on how the OX40–OX40L interaction regulates T-cell tolerance, peripheral T-cell homeostasis, and T-cell-mediated inflammatory diseases.