Article | Published:

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

Nature Medicine volume 21, pages 467475 (2015) | Download Citation

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.

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Acknowledgements

The authors thank A. Sams and S. Tullin from Novo Nordisk for providing high-molecular-weight recombinant adiponectin. We are grateful to N. Shimwell and D. Ward for assistance with mass spectrometry, and to G. Pui Choy for her help with animal experiments (all from the University of Birmingham, UK). Thanks also to N. Hogg (Cancer Research UK, London Research Institute, UK) for the activation epitope–sensitive anti-LFA-1 antibody, KIM127. We also thank C. McDonnel (GE Healthcare) for her help with the Biacore experiments and R.A. Kingsley for the Salmonella Typhimurium strain SL3261 (Wellcome Trust Sanger Institute, Cambridge, UK). We also thank D. Hardie for helping with the automated cell sorting (University of Birmingham, UK) and the University of Bristol Flow Cytometry Facility. We thank P. Nightingale (University Hospitals Birmingham NHS Trust) for advice on statistical analysis. This work was supported by grants from Diabetes UK (P.N., G.E.R.) (097825/Z/11/A), the Wellcome Trust (P.N., G.E.R.; ISSF 12/13-097825/Z/11/A), an Early Career Award from the Society for Endocrinology (M.C.), the Medical Research Council (CIC 12011) a senior fellowship for L.S.K.W. (G0802382) and the Juvenile Diabetes Research Foundation (P.N., G.E.R.; 5-2013-207). Work in the laboratories of G.E.R. is supported by the British Heart Foundation at Project grant (PG/11/49/28983) and Programme grant (RG/12/7/29693) level. H.M.M. was supported by an Arthritis Research UK Career Development Fellowship (19899). A.K. was supported by a National Institute for Health Research, Research for Patient Benefit (PB-PG-0609-19093). F.B. is supported by a Wellcome Trust Clinician Scientist Fellowship. A.F. was supported by an Arthritis Research UK Clinician Scientist Fellowship (18547). The research leading to the rheumatoid arthritis subject data was funded within the FP7 HEALTH programme under the grant agreement FP7-HEALTH-F2-2012-305549. This report is independent research which was partly supported by the National Institute for Health Research/Wellcome Trust Clinical Research Facility at University Hospitals Birmingham NHS Foundation Trust. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.

Author information

Author notes

    • Myriam Chimen
    •  & Helen M McGettrick

    These authors contributed equally to this work.

    • Parth Narendran
    •  & G Ed Rainger

    These authors jointly directed this work.

Affiliations

  1. School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.

    • Myriam Chimen
    • , Bonita Apta
    • , Sahithi J Kuravi
    • , Clara M Yates
    • , Amy Kennedy
    • , Arjun Odedra
    • , Mohammed Alassiri
    • , Matthew Harrison
    • , Joseph Robinson
    • , Neena Kalia
    • , Gerard B Nash
    • , Parth Narendran
    •  & G Ed Rainger
  2. 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.

    • Helen M McGettrick
    • , Francesca Barone
    • , Saba Nayar
    • , Karim Raza
    • , Andrew Filer
    •  & Christopher D Buckley
  3. Department of Diabetes, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

    • Amy Kennedy
    •  & Parth Narendran
  4. School of Cancer Sciences, University of Birmingham, Birmingham, UK.

    • Ashley Martin
  5. Department of Rheumatology, Sandwell and West Birmingham Hospitals National Health Service (NHS) Trust, Birmingham, UK.

    • Francesca Barone
    • , Karim Raza
    •  & Christopher D Buckley
  6. School of Immunity and Infection, University of Birmingham, Birmingham, UK.

    • Jessica R Hitchcock
    •  & Adam F Cunningham
  7. Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

    • Andrew Filer
  8. Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol, UK.

    • David A Copland
    •  & Andrew D Dick
  9. National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, Bristol, UK.

    • Andrew D Dick
  10. University College London (UCL) Institute of Ophthalmology, London, UK.

    • Andrew D Dick
  11. University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

    • Andrew D Dick
  12. School of Clinical Sciences, University of Bristol, Bristol, UK.

    • Andrew D Dick
  13. Institute of Immunity and Transplantation, UCL Medical School, Royal Free Campus, London, UK.

    • Lucy S K Walker

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Contributions

M.C. conceived and performed experiments, analyzed and interpreted the data, and co-wrote the manuscript. H.M.M. conceived, performed experiments, analyzed and interpreted the data. B.A., S.J.K., C.M.Y., A.K., A.O., M.A., M.H., S.N., J.R.H., D.A.C. and J.R. performed experiments and analyzed the data. A.M., F.B., A.F.C., K.R., A.F., D.A.C., A.D.D., N.K., L.S.K.W., C.D.B. and G.B.N. organized and conducted the study, including analysis, data interpretation and critique of the manuscript. K.R. and A.F. recruited and diagnosed patients in early arthritis clinics, and acquired the clinical data. P.N. conceived, designed and organized the T1D study and analyzed and interpreted the data. G.E.R. conceived, designed, organized and conducted the study, including analysis and interpretation of data, and co-wrote the manuscript.

Competing interests

M.C., H.M.M., P.N. and G.E.R. hold patents for the therapeutic and diagnostic use of PEPITEM (WO2013/104928) and cadherin-15 (WO2015/001356) in autoimmune disease, chronic inflammatory disease and other diseases in which T cells contribute to pathogenesis, as well as for the use of adipoRs expression as a biomarker for rheumatoid arthritis (WO2014/080204). The other authors have no competing financial interests to declare.

Corresponding authors

Correspondence to Parth Narendran or G Ed Rainger.

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