title: Targeting of a T cell agonist peptide to lysosomes by DNA vaccination induces tolerance in the nonobese diabetic mouse.
abstract: CD4 T cells are crucial effectors in the pathology of type 1 diabetes (T1D). Successful therapeutic interventions for prevention and cure of T1D in humans are still elusive. Recent research efforts have focused on the manipulation of T cells by treatment with DNA. In this paper, we studied the effects of a DNA treatment strategy designed to target antigenic peptides to the lysosomal compartment on a monospecific T cell population termed 2.5mi(+) T cells that shares reactivity with the diabetogenic T cell clone BDC-2.5 in the NOD mouse. MHC class II tetramer analysis showed that repeated administrations were necessary to expand 2.5mi(+) T cells in vivo. This expansion was independent of Ag presentation by B cells. A single peptide epitope was sufficient to induce protection against T1D, which was not due to Ag-specific T cell anergy. Typical Th2 cytokines such as IL-10 or IL-4 were undetectable in 2.5mi(+) T cells, arguing against a mechanism of immune deviation. Instead, the expanded 2.5mi(+) T cell population produced IFN-γ similar to 2.5mi(+) T cells from naive mice. Protection against T1D by DNA treatment was completely lost in NOD.CD28(-/-) mice which are largely deficient of natural regulatory T cells (Treg). Although Ag-specific Foxp3(+) Treg did not expand in response to DNA treatment, diabetes onset was delayed in Treg-reconstituted and DNA-treated NOD.SCID mice. These observations provide evidence for a Treg-mediated protective mechanism that is independent of the expansion or de novo generation of Ag-specific Treg.
authors.affiliation: Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Elisa I
authors.initials: EI
authors.lastname: Rivas
authors.forename: John P
authors.initials: JP
authors.lastname: Driver
authors.forename: Nahir
authors.initials: N
authors.lastname: Garabatos
authors.forename: Maximiliano
authors.initials: M
authors.lastname: Presa
authors.forename: Conchi
authors.initials: C
authors.lastname: Mora
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodriguez
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
authors.forename: Thomas
authors.initials: T
authors.lastname: Stratmann
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D004306:Dose-Response Relationship, Immunologic; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D007108:Immune Tolerance / Q000235:genetics; D008247:Lysosomes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000008:administration & dosage / Q000819:agonists* / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000819:agonists* / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D010446:Peptide Fragments; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic