Circulating β cell-specific CD8+ T cells restricted by high-risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes

Abstract

Summary In type 1 diabetes (T1D), autoreactive cytotoxic CD8+ T cells are implicated in the destruction of insulin‐producing β cells. The HLA‐B*3906 and HLA‐A*2402 class I genes confer increased risk and promote early disease onset, suggesting that CD8+ T cells that recognize peptides presented by these class I molecules on pancreatic β cells play a pivotal role in the autoimmune response. We examined the frequency and phenotype of circulating preproinsulin (PPI)‐specific and insulin B (InsB)‐specific CD8+ T cells in HLA‐B*3906+ children newly diagnosed with T1D and in high‐risk HLA‐A*2402+ children before the appearance of disease‐specific autoantibodies and before diagnosis of T1D. Antigen‐specific CD8+ T cells were detected using human leucocyte antigen (HLA) class I tetramers and flow cytometry was used to assess memory status. In HLA‐B*3906+ children with T1D, we observed an increase in PPI5–12‐specific transitional memory CD8+ T cells compared to non‐diabetic, age‐ and HLA‐matched subjects. Furthermore, PPI5–12‐specific CD8+ T cells in HLA‐B*3906+ children with T1D showed a significantly more antigen‐experienced phenotype compared to polyclonal CD8+ T cells. In longitudinal samples from high‐risk HLA‐A*2402+ children, the percentage of terminal effector cells within the InsB15–24‐specific CD8+ T cells was increased before diagnosis relative to samples taken before the appearance of autoantibodies. This is the first study, to our knowledge, to report HLA‐B*3906‐restricted autoreactive CD8+ T cells in T1D. Collectively, our results provide evidence that β cell‐reactive CD8+ T cells restricted by disease‐associated HLA class I molecules display an antigen‐experienced phenotype and acquire enhanced effector function during the period leading to clinical diagnosis, implicating these cells in driving disease.

Bioinformatics analysis of gene expression profiles of Inclusion body myositis

“…This finding is consistent with previous studies stipulating that the HLA locus is the strongest risk allele in the development of IBM 10 . HLA alleles are known to be associated with a variety of autoimmune diseases, such as systemic lupus erythematosus (SLE), 11 type 1 diabetes mellitus 12 and rheumatoid arthritis(RA) 13 . The genes products in this region play a fundamental role in the immune response.…”

Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets

“…Interestingly, in recent onset cases, different islets harbored different reactivities, which could reflect different stages of the autoimmune process. More recently, a high proportion of preproinsulin (PPI) specific cells have been detected in the islets of donors with T1D (17,18), confirming previous data obtained from blood samples and highlighting the role of PPI as one of the most prominent antigens in disease pathogenesis (15,(19)(20)(21)(22). Attempts to detect neoantigens in situ have not been reported so far but are on the horizon.…”

“…In addition, their potential role in sustaining the effector functions of CD8+ T-cells should not be neglected (14). Both CD4+ and CD8+ Tcell populations decline with beta-cell loss, suggesting that their presence is driven by a beta-cell antigen (11,12,15). However, the exact role infiltrating T-cells play in the pathogenesis of the disease remains to be determined both in terms of specificity and function.…”

New Insights Into the Role of Autoreactive CD8 T Cells and Cytokines in Human Type 1 Diabetes

“…On the other hand, other studies demonstrated no significant differences between T1D and control individuals in the frequencies of circulating CD8 T cells reactive to multiple A*02:01-restricted beta-cell epitopes (PPI 14 (3,4,6,10). However, beta cell-specific CD8 T cells are more differentiated in patients with newly diagnosed T1D compared to healthy controls (6), and memory T cell subsets were enriched within PPI 5-12 -specific CD8 T cell populations in HLA-B*39:06 + children with newly diagnosed T1D, but not in healthy control subjects (10). Overall, these studies suggest that phenotypic subset analysis of such circulating autoreactive T cells could help to identify patients with T1D.…”