Abstract

Human soluble interleukin-7 receptor (sIL7R)a circulates in high molar excess compared with IL-7, but its biology remains unclear. We demonstrate that sIL7Ra has moderate affinity for IL-7 but does not bind thymic stromal lymphopoietin. Functionally, sIL7Ra 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 sIL7Ra 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 sIL7Ra and also demonstrate a potentiating effect of sIL7Ra 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 sIL7Ra 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 sIL7Ra potentiates IL-7 bioactivity and provides a basis to explain the increased risk of autoimmunity observed in individuals with genotype-induced elevations of sIL7Ra.

View details for DOI 10.1073/pnas.1222303110

View details for Web of Science ID 000319327700009

View details for PubMedID 23610432