title: B cell-derived IL-10 suppresses inflammatory disease in Lyn-deficient mice.
abstract: Lyn kinase deficient mice represent a well established genetic model of autoimmune/autoinflammatory disease that resembles systemic lupus erythematosus. We report that IL-10 plays a crucial immunosuppressive role in this model, modulating the inflammatory component of the disease caused by myeloid and T-cell activation. Double-mutant lyn(-/-)IL-10(-/-) mice manifested severe splenomegaly and lymphadenopathy, dramatically increased proinflammatory cytokine production, and severe tissue inflammation. Single-mutant lyn(-/-)mice showed expansion of IL-10-producing B cells. Interestingly, WT B cells adoptively transferred into lyn(-/-) mice showed increased differentiation into IL-10-producing B cells that assumed a similar phenotype to endogenous lyn(-/-) IL-10-producing B cells, suggesting that the inflammatory environment present in lyn(-/-) mice induces IL-10-producing B-cell differentiation. B cells, but not T or myeloid cells, were the critical source of IL-10 able to reduce inflammation and autoimmunity in double mutant lyn(-/-)IL-10(-/-) mice. IL-10 secretion by B cells was also crucial to sustain transcription factor Forkhead Box P3 (Foxp3) expression in regulatory T cells during disease development. These data reveal a dominant immunosuppressive function of B-cell-derived IL-10 in the Lyn-deficient model of autoimmunity, extending our current understanding of the role of IL-10 and IL-10-producing B cells in systemic lupus erythematosus.
authors.affiliation: Department of Laboratory Medicine and Microbiology/Immunology, University of California, San Francisco, CA 94143, USA. scapini@univr.it
authors.forename: Patrizia
authors.initials: P
authors.lastname: Scapini
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Lamagna
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Hu
authors.forename: Karim
authors.initials: K
authors.lastname: Lee
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Tang
authors.forename: Anthony L
authors.initials: AL
authors.lastname: DeFranco
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
mesh_terms: D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008206:Lymphatic Diseases / Q000209:etiology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology; D013163:Splenomegaly / Q000209:etiology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics
chemical_list: D016207:Cytokines; C556062:IL10 protein, mouse; D018836:Inflammation Mediators; D016753:Interleukin-10; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases