T-cell anergy: from phenotype to genotype and back.

For many decades, anergy has been used as a descriptive term to describe a state of antigen-specific unresponsiveness. A better understanding of this phenotype was revealed in the 1980s using in vitro model systems. These model systems demonstrated that protein synthesis and mobilization of Ca2+ was required leading to the pursuit of a novel gene(s) that would be unique to the anergy phenotype. Several putative "anergy factors" have been suggested. In this review, we provide an overview of the anergy phenotype and proposed anergy-related genes. To date, no single gene has been described that would completely fulfill the criteria of an "anergy factor." We review work from our laboratory describing a novel gene that we have termed Gene Related to Anergy In Lymphocytes (GRAIL) that is upregulated in T cells anergized in vitro and in vivo and, following transduction into T cells, reiterates the anergy phenotype.