Selenium is known to enhance immune function, but its mechanism of action is not known. To elucidate the role of selenoproteins (SPs) in T cell immunity, we used loxP-Cre technology to specifically target the removal of the selenocysteine (Sec) tRNA gene (Δtrsp). Flow cytometric analysis in Δtrsp mice revealed that maturation of CD4+ and CD8+ T cells in thymus were reduced by 50% (p<0.0001). In spleen and lymph nodes, the CD8+ T cell population was reduced by approximately 45%. In vitro stimulation of Δtrsp T cells with anti-CD3/CD28 had no effect on IL-2 production, but cell proliferation was reduced by 98% (p<0.0001) and they also underwent greater apoptosis. Furthermore, Δtrsp T cells exhibit a reduced IL2-R expression and defective phosphorylation of p44/p42 MAPK which is involved in signaling cell proliferation. IL-4 and IL-10 production was reduced by 75% (p<0.05, p<0.01, respectively) indicating that the lack of SPs in T cell may impair Th2 immunity. NP-OVA immunized Δtrsp mice have reduced levels of serum Ig. Findings thus far suggest that SPs are essential for normal T cell development, TCR signaling and T cell dependent immunity. We predict and are investigating: 1) SPs through their redox potential properties protect T cells from ROS generated during signaling events of immune response, and 2) the Δtrsp T cell mice are immunocompromised. This research was supported by the Intramural Research Program of the NIH, NCI.