OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells

It is important to understand which molecules are essential for long-lived immunity. We show that OX40 (CD134) is required with CD28 for the survival of CD4 T cells following antigen-driven expansion. In contrast to CD28(-/-) T cells, which show defects early, OX40(-/-)T cells are relatively unimpaired in IL-2 production, cell division, and expansion. However, OX40(-/-) T cells fall to maintain high levels of Bci-xL and Bcl-2 4-8 days after activation, and undergo apoptosis. Conversely, OX40 stimulation promotes Bcl-xL and Bcl-2 and suppresses apoptosis. Moreover, retroviral transduction of OX40(-/-) T cells with Bcl-xL or Bcl-2 reverses their survival defect. Thus, a temporal relationship exists between CD28 and OX40, with OX40 being a critical regulator of antigen-driven T cell survival.