Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity

Human soluble interleukin-7 receptor (sIL7R)alpha circulates in high molar excess compared with IL-7, but its biology remains unclear. We demonstrate that sIL7R alpha has moderate affinity for IL-7 but does not bind thymic stromal lymphopoietin. Functionally, sIL7R alpha competes with cell-associated IL-7 receptor to diminish excessive IL-7 consumption and, thus, enhances the bioactivity of IL-7 when the cytokine is limited, as it is presumed to be in vivo. IL-7 signaling in the presence of sIL7R alpha also diminishes expression of CD95 and suppressor of cytokine signaling 1, both regulatory molecules. Murine models confirm diminished consumption of IL-7 in the presence of sIL7R alpha and also demonstrate a potentiating effect of sIL7R alpha on IL-7-mediated homeostatic expansion and experimental autoimmune encephalomyelitis exacerbation. In multiple sclerosis and several other autoimmune diseases, IL7R genotype influences susceptibility. We measured increased sIL7R alpha levels, as well as increased IL-7 levels, in multiple sclerosis patients with the predisposing IL7R genotype, consistent with diminished IL-7 consumption in vivo. This work demonstrates that sIL7R alpha potentiates IL-7 bioactivity and provides a basis to explain the increased risk of autoimmunity observed in individuals with genotype-induced elevations of sIL7R alpha.