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 Kb/A12-21-monospecific CD8+ T cells and autoimmune diabetes. A pCI/ppinsΔA12-21 vector (lacking the critical Kb/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.
Highlights
IntroductionDiabetes development was accelerated in female and male NOD mice after preproinsulin (ppins)-specific DNA immunization, whereas glutamic acid decarboxylase-specific vector DNA conferred partial protection[33,34]
To investigate whether the modified ppinsΔA12-21 antigen induces a prophylactic immunity, we immunized PD-L1−/− or PD-1−/− mice with pCI/ppinsΔA12-21 followed by an injection with the diabetogenic pCI/ppins vector at day 12 post vaccination
Vaccination of mice with a Hepatitis B Virus (HBV) core antigen-expressing pCI/C vector did not suppress diabetes induction by a subsequent injection of pCI/ppins (Fig. 1e) and, vice versa, the injection of pCI/ppinsΔA12-21 did not affect the priming of HBV core (Kb/ C93-100)-specific CD8+ T cells by a subsequent injection of the pCI/C vector (Supplementary Fig. S2)
Summary
Diabetes development was accelerated in female and male NOD mice after preproinsulin (ppins)-specific DNA immunization, whereas glutamic acid decarboxylase-specific vector DNA conferred partial protection[33,34] It is largely unknown why certain antigens or antigen domains either stimulate diabetogenic effector T cells or induce immunosuppressive Treg cells. We hypothesized that the mutant pCI/ppinsΔA 12-21 vector could elicit a prophylactic, Treg cell-mediated immunity in PD-L1−/− and PD-1−/− mice and protect them from autoimmune diabetes induced by a subsequent injection of the diabetogenic pCI/ppins vector This model allowed us to explore systematically under well-controlled experimental conditions the induction of ppins-specific Treg cells and the suppression of Kb/A12-21-monospecific effector CD8+ T cells and autoimmune diabetes
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