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

Myriam Chimen, Helen M McGettrick, Bonita Apta, Sahithi J Kuravi, Clara M Yates, Amy Kennedy, Arjun Odedra, Mohammed Alassiri, Matthew Harrison, Ashley Martin, Francesca Barone, Saba Nayar, Jessica R Hitchcock, Adam F Cunningham, Karim Raza, Andrew Filer, Dave A Copland, Andrew D Dick, Joseph Robinson, Neena KaliaLucy S K Walker, Christopher D Buckley, Gerard B Nash, Parth Narendran, G Ed Rainger

Research output: Contribution to journalArticle (Academic Journal)peer-review

55 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)467–475
JournalNature Medicine
Volume21
Early online date20 Apr 2015
DOIs
Publication statusPublished - 1 May 2015

Structured keywords

  • Brain and Behaviour
  • Nutrition and Behaviour

Fingerprint

Dive into the research topics of 'Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in autoimmune and chronic inflammatory disease'. Together they form a unique fingerprint.

Cite this