CD4 T cell effector functions are critical for protective immunity but can also drive pathological inflammation. The costimulatory receptor OX40 (CD134) enhances CD4 T cell expansion, survival, and memory formation, though its role in effector differentiation is not fully defined. Using monoclonal and polyclonal adoptive transfer models, this study demonstrates that OX40 signaling directly promotes CD4 T cell effector differentiation independent of enhanced survival. OX40 induces early effector cytokine production, requires IL-2 receptor signaling, and enhances cytokine responsiveness without dependence on CD28, CD40, or T-bet. These findings identify OX40 as a key regulator of CD4 T cell effector differentiation.
