title: Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity.
abstract: 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.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Wangko
authors.initials: W
authors.lastname: Lundström
authors.forename: Steven
authors.initials: S
authors.lastname: Highfill
authors.forename: Scott T R
authors.initials: ST
authors.lastname: Walsh
authors.forename: Stephanie
authors.initials: S
authors.lastname: Beq
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Morse
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015551:Autoimmunity; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D005260:Female; D005838:Genotype; D006801:Humans; D015851:Interleukin-7 / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology; D011110:Polymorphism, Genetic; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain
keywords: immunology; soluble receptors; tolerance