title: The tyrosine kinase Lyn limits the cytokine responsiveness of plasma cells to restrict their accumulation in mice.
abstract: Maintenance of an appropriate number of plasma cells, long-lived antibody-producing cells that are derived from B cells, is essential for maintaining immunological memory while limiting disease. Plasma cell survival relies on extrinsic factors, the limited availability of which determines the size of the plasma cell population. Mice deficient in the nonreceptor tyrosine kinase Lyn are prone to an autoimmune disease that is characterized by inflammation and an excess of plasma cells (plasmacytosis). We demonstrated that the plasmacytosis was intrinsic to B cells and independent of inflammation. We also showed that Lyn attenuated signaling by signal transducer and activator of transcription 3 (STAT3) and STAT5 in response to the cytokines interleukin-6 (IL-6) and IL-3, respectively, in two previously uncharacterized plasma cell signaling pathways. Thus, in the absence of Lyn, the survival of plasma cells was improved, which enabled the plasma cells to become established in excess numbers in niches in vivo. These data identify Lyn as a key regulator of survival signaling in plasma cells, limiting plasma cell accumulation and autoimmune disease susceptibility.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. Department of Experimental Medicine, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Simona
authors.initials: S
authors.lastname: Infantino
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. Department of Experimental Medicine, University of Melbourne, Parkville, Victoria 3052, Australia. Centre for Inflammatory Diseases, Southern Clinical School, Monash Medical Centre, Clayton, Victoria 3800, Australia.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. Department of Experimental Medicine, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Walker
authors.affiliation: Department of Immunology, Alfred Medical Research and Education Precinct, Monash University, Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Mhairi J
authors.initials: MJ
authors.lastname: Maxwell
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. Department of Experimental Medicine, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Light
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. Department of Experimental Medicine, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Kristy
authors.initials: K
authors.lastname: O'Donnell
authors.affiliation: Department of Immunology, Alfred Medical Research and Education Precinct, Monash University, Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tsantikos
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. Department of Experimental Medicine, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Victor
authors.initials: V
authors.lastname: Peperzak
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. Department of Experimental Medicine, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Toby
authors.initials: T
authors.lastname: Phesse
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. Department of Experimental Medicine, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.affiliation: Department of Immunology, Alfred Medical Research and Education Precinct, Monash University, Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
authors.affiliation: Department of Immunology, Alfred Medical Research and Education Precinct, Monash University, Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hibbs
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. Department of Experimental Medicine, University of Melbourne, Parkville, Victoria 3052, Australia. Department of Immunology, Alfred Medical Research and Education Precinct, Monash University, Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Fairfax
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. Department of Experimental Medicine, University of Melbourne, Parkville, Victoria 3052, Australia. tarlinton@wehi.edu.au.
authors.forename: David M
authors.initials: DM
authors.lastname: Tarlinton
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002470:Cell Survival / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism*; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D007156:Immunologic Memory / Q000276:immunology*; D051379:Mice; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D001973:Bromodeoxyuridine