Dose-dependent induction of distinct anergic phenotypes: Multiple levels of T cell anergy

T cell anergy has been proposed as one of the mechanisms underlying periphe ral T cell tolerance. In recent years, the functional relevance of T cell a nergy has been studied extensively in vitro and in vivo, using different sp ecies, cell systems, and ways to induce anergy, Although these studies conc urred about the induction of unresponsiveness, conflicting findings were ob tained with respect to the function of anergic T cells and to the persisten ce of T cell anergy, In the present study, T cell anergy was induced throug h T-T presentation of the specific Ag by rat MHC class II+ T cells in the a bsence of professional APC, We show that, depending on the Ag dose with whi ch T cells were incubated, distinct anergic phenotypes were induced. Incuba tion of T cell clones with a low (suboptimal) Ag dose induced hyporesponsiv eness. Incubation with a higher (optimal) Ag dose induced an anergic state capable of exerting immunoregulatory effects. Incubation with a high (supra optimal) Ag dose led to an anergic suppressive phenotype that was persisten t and was not reversed by APC, Ag, and rIL-2. These findings demonstrate th at T cell anergy is not confined to a singlestate of functional inactivatio n. Instead, multiple levels of T cell anergy exist. Thus, anergic T cells c an contribute to the regulation of the immune response either in a persiste nt and active manner or in a passive manner, depending on their level of T cell anergy.