WW domain-containing oxidoreductase regulates T cell activation 9024

Description T cell-mediated immunity is a central component in the immune system. Stimulation of T cell receptor (TCR) is crucial for T cell activation and proliferation. Human WWOX gene resides within a common chromosomal fragile site FRA16D and encodes a tumor suppressor WW domain-containing oxidoreductase. We recently found that WWOX plays an important role in regulating TCR signaling for modulating T cell activation and proliferation. By propidium iodide staining and 5-bromo-2’-deoxyuridine labeling, we determined that cell proliferation was increased in Wwox-/- mouse splenocytes compared with the wild-type controls after stimulation with anti-CD3 antibody for 36 h. Nevertheless, after 60-h stimulation, decreased cell proliferation and increased cell death were observed in Wwox-/- splenic T cells as compared with Wwox+/+ cells. We detected comparable levels of CD3 and CD28 molecules in Wwox+/+ and Wwox-/- splenic T cells, suggesting that dysregulation of T cell activation and growth is not due to alteration of CD3 and CD28 expression in Wwox-deficient cells. Moreover, protein phosphorylation of signaling molecules after TCR triggering was examined in mouse splenic T cells and human Jurkat T cell line. We demonstrated that WWOX deficiency led to increased phosphorylation of ERK and NF-kB after TCR stimulation. Together, our data reveal that loss of fragile WWOX gene causes dysregulation of T cell activation, suggesting a novel function of WWOX in controlling immune cell activation.