OX40 Promotes Bcl-xL and Bcl-2 Expression and Is Essential for Long-Term Survival of CD4 T Cells

Abstract

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 fail to maintain high levels of Bcl-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.

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

“…Contrary to Treg cells, effector T cells express OX40 only upon activation [11,59]. We found that Tem cells, representing the most abundant TIL subset, highly expressed OX40.…”

“…OX40 is a costimulatory molecule constitutively expressed by Treg cells and expressed upon activation by T effector (Teff) cells. Triggering of OX40 has opposite effects on these two T-cell populations: Treg cells are inhibited in their suppressive functions [3][4][5][6], while Teff cells are stimulated to proliferate, survive and gain memory phenotype [7][8][9][10][11]. Treatment of different types of mouse transplantable tumors with the mAb OX86, the agonist of OX40, favors tumor rejection thanks to its double effect on Treg and Teff cells [3,12].…”

Intracellular Signals of T Cell Costimulation

“…However, whether or not this regulation was dependent on mammalian target of rapamycin pathway is still controversial (13,75). CD28 also promotes expression of bcl-2, bfl-1 (A1), and myeloid cell leukemia sequence 1 (mcl-1) to regulate T cell survival (76)(77)(78).…”

“…OX40 regulates T cell survival by sustaining PKB mediated expression of bcl-2 and bcl-xL (15,76). Upon interaction with its ligand--OX40L, the cytoplasmic tail of OX40 associates with an adapter protein TRAF2 (79) to mediate signal transduction, probably through PI3K/PKB/ NF-κB pathway then regulates expression of bcl-xL, A1, and bcl-2 that controls T cell longevity (4).…”

“…The molecular targets of OX40 that regulate memory development is still unclear, but OX40 sustains expression of bcl-xL, which controls long-term T cell survival, suggesting that bcl-xL might also mediate memory T cell development (76). To confirm this, retroviral expression of bcl-xL in tumor-reactive CD8 + T cells conferred greatly enhanced tumor protection following adoptive transfer, indicating bcl-xL would be the target of OX40, which involves memory T cell development (88,89).…”