In Vivo Induction of Functionally Suppressive Induced Regulatory T Cells from CD4+CD25- T Cells Using an Hsp70 Peptide

• Published in: PloS one Vol. 10; no. 6; p. e0128373
• Main Authors: van Herwijnen, Martijn J C, van der Zee, Ruurd, van Eden, Willem, Broere, Femke
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.06.2015; Public Library of Science (PLoS)
• Subjects: Adoptive transfer; Animals; Antigens; Arthritis; Autoimmune diseases; Autoimmune Diseases - immunology; Autoimmune Diseases - mortality; Autoimmune Diseases - pathology; CD25 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Epigenetics; Epitopes; Epitopes, T-Lymphocyte - administration & dosage; Epitopes, T-Lymphocyte - immunology; Experiments; Flow cytometry; Heat shock proteins; Homeostasis; HSP70 Heat-Shock Proteins - administration & dosage; HSP70 Heat-Shock Proteins - immunology; Hsp70 protein; Immune response; Immunization; Immunology; Immunoregulation; In vivo methods and tests; Infectious diseases; Inflammation; Inflammation - immunology; Inflammation - pathology; Interleukin-2 Receptor alpha Subunit - immunology; Interleukin-2 Receptor alpha Subunit - metabolism; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Mice; Peptides; Peptides - administration & dosage; Peptides - immunology; Regulation; T cell receptors; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Thymus; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0128373

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.