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 alpha chain (IL-71R alpha), IL-2 receptor alpha chain (IL-21R alpha), and common gamma chain (gamma c), and did not express cytotoxic T-lymphocyte-associated protein 4, but expressed IL-15R alpha. 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-7R alpha, IL-2R alpha, and gamma c. 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.