Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1038/nm.3842

Type

Journal article

Journal

Nat med

Publication Date

05/2015

Volume

21

Pages

467 - 475

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