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 sur- vival 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 in- duced 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 sur- vival, but not T-cell anergy induction, was dependent on direct cell contacts between T cells and irradiated periph- eral blood mononuclear cells. The anergic T cells exhib- ited no or very low expression of IL-7 receptor chain (IL-7R), IL-2 receptor chain (IL-2R), and common chain (c), and did not express cytotoxic T-lymphocyte- associated protein 4, but expressed IL-15R. 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 reexpres- sions of IL-7R, IL-2R, and c. The anergy induction by IL-7 and restoration of responsiveness by IL-15 suggest novel mechanisms for regulation of helper T-cell re- sponses, induction of peripheral tolerance, and breakdown of T-cell self-tolerance. Human Immunology 66, 677-687 (2005). © American Society for Histocompatibility and Immunogenetics, 2005. Published by Elsevier Inc.