title: Systemic autoimmunity and lymphoproliferation are associated with excess IL-7 and inhibited by IL-7Rα blockade.
abstract: Lupus is characterized by disturbances in lymphocyte homeostasis, as demonstrated by the marked accumulation of activated/memory T cells. Here, we provide evidence that proliferation of the CD8+ precursors for the accumulating CD4⁻CD8⁻ T cells in MRL-Fas(lpr) lupus-predisposed mice is, in part, driven by commensal antigens. The ensuing lymphadenopathy is associated with increased production of IL-7 due to expansion of fibroblastic reticular cells, the primary source of this cytokine. The excess IL-7 is not, however, consumed by CD4⁻CD8⁻ T cells due to permanent down-regulation of IL-7Rα (CD127), but instead supports proliferation of autoreactive T cells and progression of autoimmunity. Accordingly, IL-7R blockade reduced T cell activation and autoimmune manifestations even when applied at advanced disease stage. These findings indicate that an imbalance favoring production over consumption of IL-7 may contribute to systemic autoimmunity, and correction of this imbalance may be a novel therapeutic approach in lymphoproliferative and autoimmune syndromes.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Rosana
authors.initials: R
authors.lastname: Gonzalez-Quintial
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lawson
authors.forename: John C
authors.initials: JC
authors.lastname: Scatizzi
authors.forename: Joseph
authors.initials: J
authors.lastname: Craft
authors.forename: Dwight H
authors.initials: DH
authors.lastname: Kono
authors.forename: Roberto
authors.initials: R
authors.lastname: Baccala
authors.forename: Argyrios N
authors.initials: AN
authors.lastname: Theofilopoulos
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015851:Interleukin-7 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015851:Interleukin-7; D012333:RNA, Messenger; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain
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