title: In Vivo Induction of Functionally Suppressive Induced Regulatory T Cells from CD4+CD25- T Cells Using an Hsp70 Peptide.
abstract: Therapeutic peptides that target antigen-specific regulatory T cells (Tregs) can suppress experimental autoimmune diseases. The heat shock protein (Hsp) 70, with its expression elevated in inflamed tissue, is a suitable candidate antigen because administration of both bacterial and mouse Hsp70 peptides has been shown to induce strong immune responses and to reduce inflammation via the activation or induction of Hsp specific Tregs. Although two subsets of Tregs exist, little is known about which subset of Tregs are activated by Hsp70 epitopes. Therefore, we set out to determine whether natural nTregs (derived from the thymus), or induced iTregs (formed in the periphery from CD4+CD25- naïve T cells) were targeted after Hsp70-peptide immunization. We immunized mice with the previously identified Hsp70 T cell epitope B29 and investigated the formation of functional iTregs by using an in vitro suppression assay and adoptive transfer therapy in mice with experimental arthritis. To study the in vivo induction of Tregs after peptide immunization, we depleted CD25+ cells prior to immunization, allowing the in vivo formation of Tregs from CD4+CD25- precursors. This approach allowed us to study in vivo B29-induced Tregs and to compare these cells with Tregs from non-depleted immunized mice. Our results show that using this approach, immunization induced CD4+CD25+ T cells in the periphery, and that these cells were suppressive in vitro. Additionally, adoptive transfer of B29-specific iTregs suppressed disease in a mouse model of arthritis. This study shows that immunization of mice with Hsp70 epitope B29 induces functionally suppressive iTregs from CD4+CD25- T cells.
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Martijn J C
authors.initials: MJ
authors.lastname: van Herwijnen
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Ruurd
authors.initials: R
authors.lastname: van der Zee
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: van Eden
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: Broere
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D018840:HSP70 Heat-Shock Proteins; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D010455:Peptides