title: Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in autoimmune and chronic inflammatory disease.
abstract: During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues.
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Myriam
authors.initials: M
authors.lastname: Chimen
authors.affiliation: Rheumatology Research Group, Arthritis Research UK Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: McGettrick
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Bonita
authors.initials: B
authors.lastname: Apta
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Sahithi J
authors.initials: SJ
authors.lastname: Kuravi
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Clara M
authors.initials: CM
authors.lastname: Yates
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.|Department of Diabetes, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Kennedy
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Arjun
authors.initials: A
authors.lastname: Odedra
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alassiri
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Harrison
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Ashley
authors.initials: A
authors.lastname: Martin
authors.affiliation: Rheumatology Research Group, Arthritis Research UK Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.|Department of Rheumatology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Barone
authors.affiliation: Rheumatology Research Group, Arthritis Research UK Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Saba
authors.initials: S
authors.lastname: Nayar
authors.affiliation: School of Immunity and Infection, University of Birmingham, Birmingham, UK.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Hitchcock
authors.affiliation: School of Immunity and Infection, University of Birmingham, Birmingham, UK.
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
authors.affiliation: Rheumatology Research Group, Arthritis Research UK Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.|Department of Rheumatology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.
authors.forename: Karim
authors.initials: K
authors.lastname: Raza
authors.affiliation: Rheumatology Research Group, Arthritis Research UK Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.|Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Filer
authors.affiliation: Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Copland
authors.affiliation: Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol, UK.|National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology; University Hospitals Bristol NHS, Foundation Trust, and University of Bristol, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Robinson
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Neena
authors.initials: N
authors.lastname: Kalia
authors.affiliation: Institute of Immunity & Transplantation, UCL Medical School, Royal Free Campus, London, UK.
authors.forename: Lucy S K
authors.initials: LSK
authors.lastname: Walker
authors.affiliation: Rheumatology Research Group, Arthritis Research UK Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.|Department of Rheumatology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Nash
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.|Department of Diabetes, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
authors.forename: Parth
authors.initials: P
authors.lastname: Narendran
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: G Ed
authors.initials: GE
authors.lastname: Rainger
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000097:blood; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology*; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D003922:Diabetes Mellitus, Type 1 / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation; D006706:Homeostasis; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry; D054419:Receptors, Adiponectin / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*; D055815:Young Adult
chemical_list: D048948:14-3-3 Proteins; D052242:Adiponectin; D015820:Cadherins; D008246:Lysophospholipids; D010455:Peptides; D054419:Receptors, Adiponectin; C572235:YWHAZ protein, human; C060506:sphingosine 1-phosphate; D013110:Sphingosine