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

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 P...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-08, Vol.109 (35), p.14134-14139
Main Authors: van Herwijnen, Martijn J. C, Wieten, Lotte, van der Zee, Ruurd, van Kooten, Peter J, Wagenaar-Hilbers, Josée P, Hoek, Aad, den Braber, Ineke, Anderton, Stephen M, Singh, Mahavir, Meiring, Hugo D, van Els, Cécile A. C. M, van Eden, Willem, Broere, Femke
Format: Article
Language:English
Subjects:
Administration, Intranasal
Adoptive Transfer - methods
Animals
Antigens
Arthritis
Arthritis - immunology
Arthritis - metabolism
Arthritis - therapy
Autoantigens
Autoantigens - immunology
Autoantigens - metabolism
Autoimmune diseases
Autoimmune Diseases - immunology
Autoimmune Diseases - metabolism
Autoimmune Diseases - therapy
autoimmunity
Autoimmunity - immunology
Biological Sciences
disease control
Drug regulation
Epitopes
Epitopes, T-Lymphocyte - immunology
Epitopes, T-Lymphocyte - metabolism
Heat shock proteins
HSP70 Heat-Shock Proteins - immunology
HSP70 Heat-Shock Proteins - metabolism
HSP70 Heat-Shock Proteins - pharmacology
humans
Immune Tolerance - immunology
Immunization
Immunization - methods
Immunotherapy, Adoptive - methods
Inflammation
lymph nodes
Lymphocyte Activation - immunology
lymphocyte proliferation
Lymphocytes
Mice
Mice, Inbred BALB C
phenotype
Rodents
Stress, Physiological - immunology
T lymphocytes
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
tissues
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1206803109