β-cell specific T-lymphocyte response has a distinct inflammatory phenotype in children with Type 1 diabetes compared with adults

Aim To examine the hypothesis that the quality, magnitude and breadth of helper T-lymphocyte responses to beta cells differ in Type 1 diabetes according to diagnosis in childhood or adulthood. Methods We studied helper T-lymphocyte reactivity against beta-cell autoantigens by measuring production of the pro-inflammatory cytokine interferon-gamma and the anti-inflammatory cytokine interleukin-10, using enzyme-linked immunospot assays in 61 people with Type 1 diabetes (within 3 months of diagnosis, positive for HLA DRB1*0301 and/or *0401), of whom 33 were children/adolescents, and a further 91 were unaffected siblings. Results Interferon-gamma responses were significantly more frequent in children with Type 1 diabetes compared with adults (85 vs 61%; P = 0.04). Insulin and proinsulin peptides were preferentially targeted in children (P = 0.0001 and P = 0.04, respectively) and the breadth of the interferon-gamma response was also greater, with 70% of children having an interferon-gamma response to three or more peptides compared with 14% of adults (P < 0.0001). Islet beta-cell antigen-specific interleukin-10 responses were similar in children and adults in terms of frequency, breadth and magnitude, with the exception of responses to glutamic acid decarboxylase 65, which were significantly less frequent in adults. Conclusions At diagnosis of Type 1 diabetes, pro-inflammatory autoreactivity is significantly more prevalent, focuses on a wider range of targets, and is more focused on insulin/proinsulin in children than adults. We interpret this as indicating a more aggressive immunological response in the younger age group that is especially characterized by loss of tolerance to proinsulin. These findings highlight the existence of age-related heterogeneity in Type 1 diabetes pathogenesis that could have relevance to the development of immune-based therapies.