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 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.

Effects of Lactobacillus reuteri LR1 on the growth performance, intestinal morphology, and intestinal barrier function in weaned pigs

“…In this study, LR1 increased the production of cytokines IL-22 and TGF-β associated with inhibiting TLR4 expression in the ileum of weaned pigs. Previous studies showed that TGF-β down-regulates inflammatory cytokine production in monocytes and macrophages (Laine et al, 2004) and plays a role in the induction from CD4 + T cells of induced immune regulatory T cells (Stifter et al, 2016). IL-22 is produced by activated NK and T cells, and initiates innate immune responses against pathogens invasion especially in the intestinal epithelial cells (Trevejo-Nunez et al, 2016).…”

Preproinsulin Designer Antigens Excluded from Endoplasmic Reticulum Suppressed Diabetes Development in NOD Mice by DNA Vaccination

“…We previously showed that injection of pCI/ppins but not pCI/ppinsΔA 12-21 DNA into H-2 b PD-1- or PD-L1-deficient mice induced CD8 + T cell-mediated autoimmune diabetes (Figures S1B and S1C) 7, 8. However, the failure to induce CD8 + T cells in PD-1 −/− and PD-L1 −/− mice by pCI/ppinsΔA 12-21 facilitated the induction of a systemic Foxp3 + CD25 + CD4 + Treg cell immunity that suppressed diabetes development by de novo primed K b /A 12-21 -specific CD8 + T cells 18 . Similarly, pCI/GFP-ppins or pCI/NLS-ppins vectors did not induce autoimmune diabetes in PD-L1-deficient mice (Figure 3A) and efficiently suppressed CD8 + T-cell-mediated diabetes induction by a subsequent injection of the pCI/ppins vector (Figure 3B).…”

“…In line with our previous findings, injection of pCI/GFP-ppins significantly increased Foxp3 + CD25 + CD4 + Treg cell frequencies in PD-L1 −/− mice (Figure S4). 18 This confirmed that ppins antigens that primarily did not induce autoreactive CD8 + T cells are immunogenic and induced an immune-suppressive immunity that controls de novo priming and/or expansion of K b /A 12-21 -specific effector CD8 + T cells in this diabetes model 18 Figure 3Determination of the Immune-Suppressive Potential of pCI/GFP-ppins and pCI/NLS-pins in PD-L1 −/− Mice(A) PD-L1 −/− mice were either immunized with pCI/ppins (n = 9), pCI/GFP-ppins (n = 5), or pCI/NLS-pins alone (n = 5) (left) or immunized with pCI/GFP-ppins or pCI/NLS-pins (n = 5 per group) followed by the injection of the diabetes-inducing pCI/ppins vector at day 12 post-vaccination (right).…”

“…This suggested that priming and/or expansion of K b /B 22-29 - but not K b /A 12-21 -specific CD8 + T cells critically depended on B7.1-mediated co-stimulatory signals from tg beta cells (Figures S1B and S1C) 8, 18. However, pCI/ppinsΔA 12-21 injection into PD-1 −/− or PD-L1 −/− mice elicited a systemic Foxp3 + CD25 + CD4 + Treg cell immunity that suppressed diabetes induction by a subsequent injection of the diabetogenic pCI/ppins vector 18 …”

Elevated histone H3 acetylation is associated with genes involved in T lymphocyte activation and glutamate decarboxylase antibody production in patients with type 1 diabetes

“…Type 1 diabetes is characterized by T lymphocytes‐mediated destruction of pancreatic β‐cells, and CD4 + T lymphocytes are important in recognizing islet autoantigens, especially hybrid insulin peptides and proinsulin, and prompting pancreatic infiltration in autoimmune diabetes. Aside from T cell‐mediated immunity, the destruction of β‐cells also leads to a humoral response with production of antibodies against β‐cell autoantigens, with glutamic acid decarboxylase antibody (GADA) being the most common antibody present in autoimmune diabetes.…”