The role of OX40 in the islet allograft tolerance, especially in the absence of CD154 costimulation, remains poorly defined. In the present study, we used CD154 deficient mice to critically examine the role of OX40 in the activation of T effector cells and Foxp3 Tregs and the effect of blocking OX40 on the induction of islet allograft tolerance. We found that blocking OX40 costimulation in CD154 deficient mice induced donor specific tolerance but stimulating OX40 resulted in prompt islet allograft rejection. We also found that OX40 differentially regulates T effector cells and Foxp3 Tregs, OX40 signaling mediates proliferation of CD154 deficient T effector cells but blocks the induction and suppressor functions of Foxp3 Tregs. Our data suggest that the role of OX40 in the induction of islet allograft tolerance involves modifying not only the T effector cells but also the Foxp3 Tregs in CD154 deficient mice.
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