Selenium (Se) is an essential micronutrient important for many aspects of human health, including optimal immune responses. The biological effects of Se are exerted mainly through its incorporation into selenoproteins as the amino acid, selenocysteine (Sec). Twenty-five selenoproteins have been identified in humans, all but one of which also exist as Sec-containing proteins in mice and rats. One selenoprotein that we have found to be important for optimal immune responses is the endoplasmic reticulum (ER) enzyme selenoprotein I (SELENOI). SELENOI expression is increased in stimulated T cells and is sensitive to levels of Se intake. The main goal of our research product is to fully understand the role that SELENOI plays in regulating T cell responses. Our central hypothesis is that SELENOI functions to synthesize phosphatidylethanolamine (PE) in the Kennedy synthesis pathway, and during activation of T cells there is increased demand for PE that requires higher levels of Se incorporated into SELENOI synthesized de novo. This in turn leads to higher levels of PE incorporated into cellular membranes. In conditions of low Se or genetic defects that reduce SELENOI expression and activity, membrane rigidity is compromised as well as other membrane properties that lead to impaired T cell signaling, proliferation, and differentiation. Our innovative studies will definitively determine the role of SELENOI in PE biosynthesis and how this affects T cell function and immune responses. We will accomplishment of the following specific aims: Specific Aim 1. To determine the role of SELENOI in PE synthesis in T cells and its requirement for establishing balanced membrane lipid composition and promoting robust TCR induced signals. Specific Aim 2. To elucidate mechanisms by which SELENOI promotes effective T cell proliferation and differentiation. Specific Aim 3. To determine the in vivo role of SELENOI in T cell responses to vaccines and a viral pathogen.