Coculture of Th Cells With Interleukin (IL)-7 in the Absence of Antigenic Stimuli Induced T-Cell Anergy Reversed by IL-15

Interleukin-7 (IL-7) is an important survival factor for T cells. We report here for the first time that it has another important role, facilitating T-cell clonal unresponsiveness, or anergy. The anergy was induced by a 20-day coculture of activated-human CD4+ T-cell clones with IL-7 and irradiated peripheral blood mononuclear cells without antigenic stimuli. T-cell survival, but not T-cell anergy induction, was dependent on direct cell contacts between T cells and irradiated peripheral blood mononuclear cells. The anergic T cells exhibited no or very low expression of IL-7 receptor α chain (IL-7Rα), IL-2 receptor α chain (IL-2Rα), and common γ chain (γc), and did not express cytotoxic T-lymphocyte-associated protein 4, but expressed IL-15Rα. Coculture for 3 to 9 days of anergic T cells with a T-cell-activating cytokine IL-15, but not IL-2, restored the responsiveness of IL-7-induced anergic T cells together with reexpressions of IL-7Rα, IL-2Rα, and γc. The anergy induction by IL-7 and restoration of responsiveness by IL-15 suggest novel mechanisms for regulation of helper T-cell responses, induction of peripheral tolerance, and breakdown of T-cell self-tolerance.