Corrigendum: Thioreductase-Containing Epitopes Inhibit the Development of Type 1 Diabetes in the NOD Mouse Model.

[This corrects the article DOI: 10.3389/fimmu.2016.00067.].

Thioreductase-Containing Epitopes Inhibit the Development of Type 1 Diabetes in the NOD Mouse Model.

Autoreactive CD4(+) T cells recognizing islet-derived antigens play a primary role in type 1 diabetes. Specific suppression of such cells therefore represents a strategic target for the cure of the disease. We have developed a methodology by which CD4(+) T cells acquire apoptosis-inducing properties on antigen-presenting cells after cognate recognition of natural sequence epitopes. We describe here that inclusion of a thiol-disulfide oxidoreductase (thioreductase) motif within the flanking residues of a single MHC class II-restricted GAD65 epitope induces GAD65-specific cytolytic CD4(+) T cells (cCD4(+) T). The latter, obtained either in vitro or by active immunization, acquire an effector memory phenotype and lyse APCs by a Fas-FasL interaction. Furthermore, cCD4(+) T cells eliminate by apoptosis activated bystander CD4(+) T cells recognizing alternative epitopes processed by the same APC. Active immunization with a GAD65 class II-restricted thioreductase-containing T cell epitope protects mice from diabetes and abrogates insulitis. Passive transfer of in vitro-elicited cCD4(+) T cells establishes that such cells are efficient in suppressing autoimmunity. These findings provide strong evidence for a new vaccination strategy to prevent type 1 diabetes.

Suppression of Immune Response to Adenovirus Serotype 5 Vector by Immunization with Peptides Containing an MHC Class II Epitope and a Thio-Oxidoreductase Motif.

The main obstacle to viral vector-mediated gene therapy remains the elicitation of an immune response to the vector, resulting in clearance of transgene and resistance to further transgenesis. Specific antibody production contributes to such immune responses. A single class II-restricted epitope of adenovirus serotype 5 (Ad5) vector hexon-6 capsid protein containing a thiol-oxidoreductase motif was used in an attempt to prevent specific antibody production in response to Ad5 vectors. We demonstrate here that such immunization carried out before intravenous administration of Ad5 vectors prevents antibody production to the ensemble of Ad5 vector proteins in both BALB/c and C57BL/6 mice. The antibody response to Ad5 is dependent on innate immune activation, seemingly involving natural killer T (NKT) cells. We observed that immunization with a class II-restricted Ad5 peptide prevents such NKT cell activation. Increased transgenesis and prolonged transgene expression result from such immunization, providing a simple protocol for improving gene therapy.

MHC Class II-Restricted Epitopes Containing an Oxidoreductase Activity Prompt CD4(+) T Cells with Apoptosis-Inducing Properties.

Abrogating an unwanted immune response toward a specific antigen without compromising the entire immune system is a hoped-for goal in immunotherapy. Instead of manipulating dendritic cells and suppressive regulatory T cells, depleting effector T cells or blocking their co-stimulatory pathways, we describe a method to specifically inhibit the presentation of an antigen eliciting an unwanted immune reaction. Inclusion of an oxidoreductase motif within the flanking residues of MHC class II epitopes polarizes CD4(+) T cells to cytolytic cells capable of inducing apoptosis in antigen presenting cells (APCs) displaying cognate peptides through MHC class II molecules. This novel function results from an increased synapse formation between both cells. Moreover, these cells eliminate by apoptosis bystander CD4(+) T cells activated at the surface of the APC. We hypothesize that they would thereby block the recruitment of cells of alternative specificity for the same autoantigen or cells specific for another antigen associated with the pathology, providing a system by which response against multiple antigens linked with the same disease can be suppressed. These findings open the way toward a novel form of antigen-specific immunosuppression.

Establishing an allergic eczema model employing recombinant house dust mite allergens Der p 1 and Der p 2 in BALB/c mice.

The major house dust mite allergens Der p 1 and Der p 2 are prevalent inducers of eczema. Der p 1 is a cysteine protease disrupting epithelial barriers, whereas Der p 2 functionally mimics the LPS-binding compound MD-2 within the TLR4 complex. In this work, we tested the percutaneous sensitizing capacity of recombinant (r) Der p 1 and Der p 2 in BALB/c mice. Mice were sensitized by percutaneous application of low (10 µg/application) and high dose (100 µg) rDer p 1 or rDer p 2, or with rDer p 1 followed by rDer p 2. Allergen-specific and total IgE antibodies were determined by ELISA. Eczema of BALB/c was classified by the itching score and corresponded to erosions. Infiltrating immune cells were identified by haematoxylin/eosin and Giemsa staining for eosinophils or mast cells, CD3 staining for T lymphocytes. Percutaneous treatments with rDer p 1, but not rDer p 2-induced specific IgG1. However, cotreatment with rDer p 1 led to increase in anti-Der p 2 IgG titres. Both allergens elicited skin erosions because of scratching, thickening of the epidermis, and eosinophil and T-cell infiltration. Our data indicate that recombinant mite allergens in the absence of adjuvant are sufficient for inducing eczema in BALB/c mice. As the enzymatic activity of an allergen might be an important cofactor for specific sensitization via the skin, Der p 1 may act as adjuvant for other allergens too. The presented mouse model is suitable for investigating the mechanisms of allergic eczema.