Regulatory T cells that recognize a ubiquitous stress-inducible self-antigen are long-lived suppressors of autoimmune arthritis

Martijn J. C. van Herwijnen, Lotte Wieten, Ruurd van der Zee, Peter J. van Kooten, Josee P. Wagenaar-Hilbers, Aad Hoek, Ineke den Braber, Stephen M. Anderton, Mahavir Singh, Hugo D. Meiring, Cecile A. C. M. van Els, Willem van Eden*, Femke Broere

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Reestablishing self-tolerance in autoimmunity is thought to depend on self-reactive regulatory T cells (Tregs). Exploiting these antigen-specific regulators is hampered by the obscure nature of disease-relevant autoantigens. We have uncovered potent disease-suppressive Tregs recognizing Heat Shock Protein (Hsp) 70 self-antigens, enabling selective activity in inflamed tissues. Hsp70 is a major contributor to the MHC class II ligandome. Here we show that a conserved Hsp70 epitope (B29) is present in murine MHC class II and that upon transfer, B29-induced CD4(+) CD25(+) Foxp3(+) T cells suppress established proteoglycan-induced arthritis in mice. These self-antigen-specific Tregs were activated in vivo, and when using Lymphocyte Activation Gene-3 as a selection marker, as few as 4,000 cells sufficed. Furthermore, depletion of transferred Tregs abrogated disease suppression. Transferred cells exhibited a stable phenotype and were found in joints and draining lymph nodes up to 2 mo after transfer. Given that (i) B29 administration by itself suppressed disease, (ii) our findings were made with wild-type (T-cell receptor nontransgenic) Tregs, and (iii) the B29 human homolog is presented by HLA class II, we are nearing translation of antigen-specific Treg activation as a promising intervention for chronic inflammatory diseases.

Original languageEnglish
Pages (from-to)14134-14139
Number of pages6
JournalProceedings of the National Academy of Sciences (PNAS)
Volume109
Issue number35
DOIs
Publication statusPublished - 28 Aug 2012

Keywords

  • TOLERANCE
  • ACTIVATION
  • VACCINATION
  • AUTOPHAGY
  • HEAT-SHOCK PROTEINS
  • PEPTIDES
  • HEAT-SHOCK-PROTEIN-70
  • PREVENTION
  • DISEASE
  • RHEUMATOID-ARTHRITIS

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