Immune regulation by OX40/OX40 ligand system

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OX40 expressed on activated T cells is known to be an important costimulatory molecule on T cell activation in vitro. However, the in vivo functional significance of the interaction between OX40 and its ligand, OX40L is still unclear. To investigate the role of OX40L during in vivo immune responses, we generated OX40L-deficient mice and a blocking anti-OX40L mAb, MGP34. OX40L expression was demonstrated on splenic B cells after CD40 and anti-IgM stimulation, while only CD40 ligation was capable of inducing OX40L on dendritic cells. OX40L-deficient and MGP34-treated mice, engendered apparent suppression of the recall reaction of T cells primed with both protein- and allo-antigens and a significant reduction in KLH-specific IgG production. The impaired T-cell-priming was also accompanied by a concomitant reduction of both Th1 and Th2 cytokines. Furthermore, antigen presenting cells (APCs) derived from the mutant mice revealed an impaired intrinsic APC function, demonstrating the importance of OX40L in both the priming and effector phases of T cell activation. Collectively, these results provide convincing evidence that OX40L, expressed on APCs, plays a critical role in antigen-specific T cell responses in vivo.Furthermore, we examined the effect of OX40L-deficiency or blockade of OX40-OX40L interaction in pathogenesis of experimental autoimmune encephalitis (EAE), which is a mouse model for human multiple sclerosis. OX40L-deficient and MGP34-treated mice showed less symptoms and rapid recovery during EAE as compared with wild type or control Ab-treated mice. These results suggest that OX40L may be functionally involved in the pathogenesis of autoimmune diseases such as EAE.