Abstract
Increasing evidence suggests that post-translational peptide splicing can play a role in the immune response under pathological conditions. This seems to be particularly relevant in Type 1 Diabetes (T1D) since post-translationally spliced epitopes derived from T1D-associated antigens have been identified among those peptides bound to Human Leucocyte Antigen (HLA) class I and II complexes. Their immunogenicity has been confirmed through CD4+ and CD8+ T cell-mediated responses in T1D patients. Spliced peptides theoretically have a large sequence variability. This might increase the frequency of viral-human zwitter peptides, i.e. peptides that share a complete sequence homology irrespective of whether they originate from human or viral antigens, thereby impinging upon the discrimination between self and non-self antigens by T cells. This might increase the risk of autoimmune responses triggered by viral infections. Since enteroviruses and other viral infections have historically been associated with T1D, we investigated whether cis-spliced peptides derived from selected viruses might be able to trigger CD8+ T cell-mediated autoimmunity. We computed in silico viral-human non-spliced and cis-spliced zwitter epitope candidates, and prioritized peptide candidates based on: (i) their binding affinity to HLA class I complexes, (ii) human pancreatic β cell and medullary thymic epithelial cell (mTEC) antigens’ mRNA expression, (iii) antigen association with T1D, and (iv) potential hotspot regions in those antigens. Neglecting potential T cell receptor (TCR) degeneracy, no viral-human zwitter non-spliced peptide was found to be an optimal candidate to trigger a virus-induced CD8+ T cell response against human pancreatic β cells. Conversely, we identified some zwitter peptide candidates, which may be produced by proteasome-catalyzed peptide splicing, and might increase the likelihood of pancreatic β cells recognition by virus-specific CD8+ T cell clones, therefore promoting β cell destruction in the context of viral infections.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease with a pivotal T cell activity
For a systematic estimation of the potential number of viral-human zwitter epitope candidates that could (i) be presented by Human Leucocyte Antigen (HLA)-I complexes, (ii) be involved in an autoimmune CD8+ T cell response in Type 1 Diabetes (T1D) patients, and (iii) be at least in part triggered by viral infection, we started from the foundations: we computed the number of 9mer peptides that might originate from human proteome, as well as those that might originate from T1D-associated viruses (Table S3)
Twelve viral-human zwitter non-spliced 9mer epitope candidates have already been eluted from HLA-I complexes and identified by mass spectrometry, and for one peptide a positive T cell assay has been described, according to the Immune Epitope Database (IEDB) (Figures 2C, D)
Summary
Type 1 diabetes (T1D) is an autoimmune disease with a pivotal T cell activity. CD4+ and CD8+ T cell-mediated responses in T1D patients play a prominent role in pancreatic b cell death, and the consequent insulin-dependent disease. The enzymes (or biochemical reactions) catalyzing their production are not fully understood, pioneer studies suggest that HIPs or HIPs’ precursors might be produced in b cell’s insulin crinosomes or professional antigen presenting cell (APC)’s lysosomes [9, 12, 13]. Their identification, is still controversial, and the employment of different mass spectrometry data analysis strategies has led to contradictory results in HIPs’ identification [12, 14]
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