title: An Arthritis-Suppressive and Treg Cell-Inducing CD4+ T Cell Epitope Is Functional in the Context of HLA-Restricted T Cell Responses.
abstract: OBJECTIVE
  We previously showed that mycobacterial Hsp70-derived peptide B29 induced B29-specific Treg cells that suppressed experimental arthritis in mice via cross-recognition of their mammalian Hsp70 homologs. The aim of the current study was to characterize B29 binding and specific CD4+ T cell responses in the context of human major histocompatibility complex (MHC) molecules.
  
  
  METHODS
  Competitive binding assays were performed to examine binding of peptide B29 and its mammalian homologs to HLA molecules. The effect of B29 immunization in HLA-DQ8-transgenic mice with proteoglycan-induced arthritis was assessed, followed by ex vivo restimulation with B29 to examine the T cell response. Human peripheral blood mononuclear cells were used to investigate the presence of B29-specific T cells with immunoregulatory potential.
  
  
  RESULTS
  The binding affinity of the B29 peptide was high to moderate for multiple HLA-DR and HLA-DQ molecules, including those highly associated with rheumatoid arthritis. This binding was considered to be functional, because B29 immunization resulted in the suppression of arthritis and T cell responses in HLA-DQ8-transgenic mice. In humans, we demonstrated the presence and expansion of B29-specific CD4+ T cells, which were cross-reactive with the mammalian homologs. Using HLA-DR4+ tetramers specific for B29 or the mammalian homolog mB29b, we showed expansion of cross-reactive T cells, especially the human FoxP3+ CD4+CD25+ T cell population, after in vitro stimulation with B29.
  
  
  CONCLUSIONS
  These results demonstrated a conserved fine specificity and functionality of B29-induced Treg cell responses in the context of the human MHC. Based on these findings, a path for translation of the experimental findings for B29 into a clinical immunomodulatory therapeutic approach is within reach.
authors.affiliation: Utrecht University, Utrecht, The Netherlands.
authors.forename: Charlotte
authors.initials: C
authors.lastname: de Wolf
authors.affiliation: Utrecht University, Utrecht, The Netherlands.
authors.forename: Ruurd
authors.initials: R
authors.lastname: van der Zee
authors.affiliation: Utrecht University, Utrecht, The Netherlands.
authors.forename: Ineke
authors.initials: I
authors.lastname: den Braber
authors.affiliation: Rush University Medical Center, Chicago, Illinois.
authors.forename: Tibor
authors.initials: T
authors.lastname: Glant
authors.affiliation: Commissariat à l'Énergie Atomique, Institut de Biologie et de Technologies de Saclay, Gif Sur Yvette, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Maillère
authors.affiliation: Commissariat à l'Énergie Atomique, Institut de Biologie et de Technologies de Saclay, Gif Sur Yvette, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Favry
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: van Lummel
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
authors.affiliation: Utrecht University, Utrecht, The Netherlands.
authors.forename: Aad
authors.initials: A
authors.lastname: Hoek
authors.affiliation: Utrecht University, Utrecht, The Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: Ludwig
authors.affiliation: Utrecht University, Utrecht, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: van Eden
authors.affiliation: Utrecht University, Utrecht, The Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: Broere
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001667:Binding, Competitive; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D002478:Cells, Cultured; D003429:Cross Reactions; D004745:Enkephalins / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D006683:HLA-DQ Antigens / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D019012:Integrin beta1 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011498:Protein Precursors / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D004745:Enkephalins; D018984:Epitopes, T-Lymphocyte; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006683:HLA-DQ Antigens; D019012:Integrin beta1; D053645:Interleukin-2 Receptor alpha Subunit; D011498:Protein Precursors; C056943:peptide B