Self-reactive T cells populate the peripheral immune system, and likely form the reservoir from which autoreactive cells are derived. We analyzed a panel of self and non-self peptides presented by HLA-DR4, a class II molecule associated with autoimmunity, by immunization of mice transgenic for HLA-DR4. Significant structural avidity for T cell recognition, as measured by MHC class II tetramer binding to CD4(+) T cells was only observed in mice immunized with the non-self antigens. T cell hybridomas were generated from mice immunized with the naturally processed self-peptide hGAD65 (552-572) and also from mice immunized with an influenza-derived non-self epitope (HA 306-318). T cells specific for the self peptide failed to bind tetramers and exhibited low functional avidity as measured by the peptide concentration required to reach half-maximum proliferation values. In contrast, T cells specific for the non-self HA (306-318) peptide exhibited high structural and functional avidity profiles. As recently described in studies of murine CD8(+) T cell function, the predominance of low avidity recognition of self-peptide epitopes may be a characteristic feature of CD4(+) T cells responding to autoantigens.
"A further analysis suggested that the weaker proliferative responses of Can f 1 and TL peptide-specific TCLs are attributed to the low frequency of TCLs with high functional TCR avidity (Fig. 2B). These results are in line with reports from other investigators, as they indicate that T cells specific to self antigens exhibit low TCR avidity whereas those specific to microbial antigens exhibit higher TCR avidity –. "
[Show abstract][Hide abstract] ABSTRACT: Lipocalin allergens form a notable group of proteins, as they contain most of the significant respiratory allergens from mammals. The basis for the allergenic capacity of allergens in the lipocalin family, that is, the development of T-helper type 2 immunity against them, is still unresolved. As immunogenicity has been proposed to be a decisive feature of allergens, the purpose of this work was to examine human CD4+ T cell responses to the major dog allergen Can f 1 and to compare them with those to its human homologue, tear lipocalin (TL). For this, specific T cell lines were induced in vitro from the peripheral blood mononuclear cells of Can f 1-allergic and healthy dog dust-exposed subjects with peptides containing the immunodominant T cell epitopes of Can f 1 and the corresponding TL peptides. We found that the frequency of Can f 1 and TL-specific T cells in both subject groups was low and close to each other, the difference being about two-fold. Importantly, we found that the proliferative responses of both Can f 1 and TL-specific T cell lines from allergic subjects were stronger than those from healthy subjects, but that the strength of the responses within the subject groups did not differ between these two antigens. Moreover, the phenotype of the Can f 1 and TL-specific T cell lines, determined by cytokine production and expression of cell surface markers, resembled each other. The HLA system appeared to have a minimal role in explaining the allergenicity of Can f 1, as the allergic and healthy subjects' HLA background did not differ, and HLA binding was very similar between Can f 1 and TL peptides. Along with existing data on lipocalin allergens, we conclude that strong antigenicity is not decisive for the allergenicity of Can f 1.
PLoS ONE 05/2014; 9(5):e98461. DOI:10.1371/journal.pone.0098461 · 3.23 Impact Factor
"The absence of a bias toward nonself sequences and toward sequences with likely low HLA-A2 binding affinity (i.e., low SYFPEITHI scores) among the peptides triggering strong responses in HLA-A2 transgenic mice suggests that this immunization strategy may be readily able to overcome self-tolerance. However, it is possible that the responding T cells displayed low T-cell receptor avidity as frequently observed at least for autoreactive CD4+ T cells (30). "
[Show abstract][Hide abstract] ABSTRACT: Type 1 diabetes results from the destruction of β-cells by an autoimmune T-cell response assisted by antigen-presenting B cells producing autoantibodies. CD8(+) T-cell responses against islet cell antigens, thought to play a central role in diabetes pathogenesis, can be monitored using enzyme-linked immunosorbent spot (ELISpot) assays. However, such assays have been applied to monitoring of adult patients only, leaving aside the large and increasing pediatric patient population. The objective of this study was twofold: 1) to develop a CD8(+) T-cell interferon-γ ELISpot assay for pediatric patients and 2) to determine whether zinc transporter 8 (ZnT8), a recently described target of autoantibodies in a majority of patients, is also recognized by autoreactive CD8(+) T cells. Using DNA immunization of humanized mice, we identified nine HLA-A2-restricted ZnT8 epitopes. Among 36 HLA-A2(+) children with diabetes, 29 responded to ZnT8 epitopes, whereas only 3 of 16 HLA-A2(+) control patients and 0 of 17 HLA-A2(-) control patients responded. Some single ZnT8 epitopes performed as well as the group of epitopes in discriminating between patients and control individuals. Thus, ZnT8 is a major CD8(+) T-cell autoantigen, and ELISpot assays display similar performance in adult and pediatric type 1 diabetes.
[Show abstract][Hide abstract] ABSTRACT: Microorganisms induce strong immune responses, most of which are specific for their encoded antigens. However, microbial infections can also trigger responses against self antigens (autoimmunity), and it has been proposed that this phenomenon could underlie several chronic human diseases, such as type 1 diabetes and multiple sclerosis. Nevertheless, despite intensive efforts, it has proven difficult to identify any single microorganism as the cause of a human autoimmune disease, indicating that the 'one organism-one disease' paradigm that is central to Koch's postulates might not invariably apply to microbially induced autoimmune disease. Here, we review the mechanisms by which microorganisms might induce autoimmunity, and we outline a hypothesis that we call the fertile-field hypothesis to explain how a single autoimmune disease could be induced and exacerbated by many different microbial infections.
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