Homeostatic regulation of T cell trafficking by a B cell derived peptide is impaired in autoimmune and chronic inflammatory disease

Research output: Contribution to journalArticle

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.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 healthy age matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Importantly, control of patient T cell trafficking is re-established by exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic I/R injury, Salmonella infection, Uveitis and Sjögren’s Syndrome, PEPITEM could reduce T cell recruitment into inflamed tissues.

Details

Original languageEnglish
Article number3842
Pages (from-to)467-475
Number of pages9
JournalNature Medicine
Volume21
Issue number5
Early online date20 Apr 2015
Publication statusPublished - 15 May 2015

Keywords

  • 14-3-3 Proteins, Adiponectin, Adult, Age Factors, Aged, Aging, Animals, Arthritis, Rheumatoid, Autoimmunity, B-Lymphocytes, Cadherins, Cell Adhesion, Cell Movement, Diabetes Mellitus, Type 1, Female, Gene Expression Regulation, Homeostasis, Human Umbilical Vein Endothelial Cells, Humans, Inflammation, Lysophospholipids, Male, Mice, Middle Aged, Peptides, Receptors, Adiponectin, Sphingosine, T-Lymphocytes, Young Adult, Chronic inflammation, autoimmune disease, trafficking, T cell