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Soluble IL7R? potentiates IL-7 bioactivity and promotes autoimmunity.

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

PROVIDER: S-EPMC3651437 | BioStudies |

REPOSITORIES: biostudies

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