| The gene related to anergy in lymphocytes (GRAIL) is an E3 ubiquitin ligase that is upregulated during, and both necessary and sufficient for, the induction of T cell anergy. In this work, we have extended studies that identified GRAIL as an essential mediator of T cell anergy in order to examine GRAIL expression and function in both anergic and regulatory T cells. First, we report preferential expression of GRAIL in CD4+CD25+FoxP3+ regulatory T cells and demonstrate that expression of GRAIL is sufficient to induce a regulatory phenotype in a T cell line. Next we developed and characterized two novel methodologies of inducing or expanding regulatory T cells using either peptide or superantigen administration in mice. The expression of GRAIL and/or FoxP3 was also characterized in these models. Additionally, we have identified a novel cytoskeletal remodeling defect in anergic T cells and identified expression of GRAIL in anergic T cells as the mediator of this defect. Finally, we report a disruption of TCR mediated signaling in GRAIL expressing T cells.;The identification of differential expression of GRAIL in phenotypically distinct CD4+ T cell subsets coupled with a link between GRAIL expression and alterations in T:APC interactions supports a novel role for GRAIL in participating in the determination of T cell fate perhaps through modification of T:APC interactions. This information provides insight into mechanisms governing T cell functional determination and suggests GRAIL as a potential target for manipulation of T cell function and fate. |
