title: Exploring the induction of preproinsulin-specific Foxp3(+) CD4(+) Treg cells that inhibit CD8(+) T cell-mediated autoimmune diabetes by DNA vaccination.
abstract: DNA vaccination is a promising strategy to induce effector T cells but also regulatory Foxp3(+) CD25(+) CD4(+) Treg cells and inhibit autoimmune disorders such as type 1 diabetes. Little is known about the antigen requirements that facilitate priming of Treg cells but not autoreactive effector CD8(+) T cells. We have shown that the injection of preproinsulin (ppins)-expressing pCI/ppins vector into PD-1- or PD-L1-deficient mice induced K(b)/A12-21-monospecific CD8(+) T cells and autoimmune diabetes. A pCI/ppinsΔA12-21 vector (lacking the critical K(b)/A12-21 epitope) did not induce autoimmune diabetes but elicited a systemic Foxp3(+) CD25(+) Treg cell immunity that suppressed diabetes induction by a subsequent injection of the diabetogenic pCI/ppins. TGF-β expression was significantly enhanced in the Foxp3(+) CD25(+) Treg cell population of vaccinated/ppins-primed mice. Ablation of Treg cells in vaccinated/ppins-primed mice by anti-CD25 antibody treatment abolished the protective effect of the vaccine and enabled diabetes induction by pCI/ppins. Adoptive transfer of Treg cells from vaccinated/ppins-primed mice into PD-L1(-/-) hosts efficiently suppressed diabetes induction by pCI/ppins. We narrowed down the Treg-stimulating domain to a 15-residue ppins76-90 peptide. Vaccine-induced Treg cells thus play a crucial role in the control of de novo primed autoreactive effector CD8(+) T cells in this diabetes model.
authors.affiliation: Department of Internal Medicine I, Ulm University Medical Center, Ulm, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Stifter
authors.affiliation: Department of Internal Medicine I, Ulm University Medical Center, Ulm, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schuster
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, Research Group of Predictive Diagnostics, University Medical Centre Greifswald, Karlsburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schlosser
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, 636921, Singapore, Singapore.|Imperial College London, London, UK.
authors.forename: Bernhard Otto
authors.initials: BO
authors.lastname: Boehm
authors.affiliation: Department of Internal Medicine I, Ulm University Medical Center, Ulm, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schirmbeck
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000032:analysis; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011498:Protein Precursors / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007328:Insulin; D011498:Protein Precursors; D019444:Vaccines, DNA; C013737:preproinsulin