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 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.
Department of Infectious Diseases and Immunology,  Utrecht University, 3584 CL Utrecht,  The Netherlands.
Martijn J C
MJ
van Herwijnen
Lotte
L
Wieten
Ruurd
R
van der Zee
Peter J
PJ
van Kooten
Josée P
JP
Wagenaar-Hilbers
Aad
A
Hoek
Ineke
I
den Braber
Stephen M
SM
Anderton
Mahavir
M
Singh
Hugo D
HD
Meiring
Cécile A C M
CA
van Els
Willem
W
van Eden
Femke
F
Broere
D000281:Administration, Intranasal; D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D001168:Arthritis / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D015551:Autoimmunity / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D007108:Immune Tolerance / Q000276:immunology*; D007114:Immunization / Q000379:methods; D016219:Immunotherapy, Adoptive / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D013312:Stress, Physiological / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D018840:HSP70 Heat-Shock Proteins