title: Peptide-activated double-negative T cells can prevent autoimmune type-1 diabetes development.
abstract: Autoimmune diseases may develop because of defective maturation, activation, differentiation and function of regulatory T cells. Previous studies have shown that exposure to donor antigen activates peripheral TCRalphabeta+CD3+CD4-CD8-NK1.1-, double-negative (DN) T cells, which specifically suppress anti-donor T cells and enhance survival of skin and heart grafts from allogeneic and xenogeneic donors. However, the role of DN T cells in preventing T cell-mediated autoimmune disease is unknown. Here, we analyzed the ability of DN T cells to recognize peptides expressed on self MHC and to suppress peptide-reactive CD8+ T cells, using the P14 mouse model that expresses a transgenic TCR specific for gp33 peptide presented on self MHC class I-Db. We found that injection of gp33 peptide resulted in increased DN and decreased CD8+ T cell numbers in the lymph nodes when compared to untreated mice. Injection of gp33, but not TCR-non-specific AV peptide, increased expression of T cell activation markers on DN T cells. Moreover, gp33-activated DN T cells suppressed proliferation of syngeneic CD8+ T cells via killing activated CD8+ T cells in an antigen-specific fashion in vitro. Furthermore, transferring gp33-activated DN T cells inhibited the development of autoimmune diabetes, suggesting that DN T cells may provide a novel therapy for T cell-mediated autoimmune diseases.
authors.affiliation: Toronto General Research Institute, University Health Network and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Ford
authors.forename: Wenhao
authors.initials: W
authors.lastname: Chen
authors.forename: Sophie
authors.initials: S
authors.lastname: Wong
authors.forename: Carmen
authors.initials: C
authors.lastname: Li
authors.forename: Ramesh
authors.initials: R
authors.lastname: Vanama
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Elford
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins