Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity.

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TitleSoluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity.
Publication TypeJournal Article
Year of Publication2013
AuthorsLundström, W, Highfill, S, Walsh, STR, Beq, S, Morse, E, Kockum, I, Alfredsson, L, Olsson, T, Hillert, J, Mackall, CL
JournalProc Natl Acad Sci U S A
Date Published2013 May 7
KeywordsAdolescent, Adult, Aged, Animals, Autoimmunity, Cell Line, Cytokines, Encephalomyelitis, Autoimmune, Experimental, Female, Genotype, Humans, Interleukin-7, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Multiple Sclerosis, Polymorphism, Genetic, Receptors, Interleukin-7, Signal Transduction, T-Lymphocytes, Young Adult

Human soluble interleukin-7 receptor (sIL7R)α circulates in high molar excess compared with IL-7, but its biology remains unclear. We demonstrate that sIL7Rα has moderate affinity for IL-7 but does not bind thymic stromal lymphopoietin. Functionally, sIL7Rα 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 sIL7Rα 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 sIL7Rα and also demonstrate a potentiating effect of sIL7Rα 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 sIL7Rα 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 sIL7Rα potentiates IL-7 bioactivity and provides a basis to explain the increased risk of autoimmunity observed in individuals with genotype-induced elevations of sIL7Rα.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID23610432
PubMed Central IDPMC3651437
Grant ListAI72142 / AI / NIAID NIH HHS / United States