What are the functional properties of human CD4+ T cells, from people with type 1 diabetes, that respond to proinsulin C-peptide?

Summary The aim of this project is to use 10X Genomics single-cell sequencing to analyse the TCR usage and epitope specificity of human CD4+ T cells that respond to C-peptide. In addition, the genes expressed by CD4+ T cells specific for C-peptide, an autoantigen, will be compared to genes expressed by CD4+ T cells, from the same donor, who respond to the microbial antigens, influenza matrix protein and/or tetanus toxoid. This work will give unprecedented new insights into the function, and TCR diversity, human CD4+ T cells specific for microbial an autoantigens.

Project Details

Type 1 diabetes (T1D) is an autoimmune disease caused by the CD4+ and CD8+ T-cell response against the insulin-secreting beta cells found in the islets of Langerhans in the pancreas (referred to as islets). Genome wide association studies have shown that the HLA alleles HLA-DQ8 and DQ2 are strongly associated with risk of developing type 1 diabetes. Since the only known function of these HLA alleles is to present peptide antigens to CD4+ T cells, this strongly implicates CD4+ T cells in the immune pathogenesis of human type 1 diabetes. Following our discovery that many human islet-infiltrating CD4+ T cells recognize epitopes derived from proinsulin C-peptide (Pathiraja et al. Diabetes 2015 & Delong et al. Science, 2016). Proinsulin is insulin’s precursor, C-peptide is produced during the processing of proinsulin to insulin. More recently we found that full-length C-peptide is an important antigen in people with type 1 diabetes (So et al PNAS 2018).

The aim of this project is to use 10X Genomics single-cell sequencing to analyse the TCR usage and epitope specificity of human CD4+ T cells that respond to C-peptide. In addition, the genes expressed by CD4+ T cells specific for C-peptide, an autoantigen, will be compared to genes expressed by CD4+ T cells, from the same donor, who respond to the microbial antigens, influenza matrix protein and/or tetanus toxoid. This work will give unprecedented new insights into the function, and TCR diversity, human CD4+ T cells specific for microbial an autoantigens. This work will lay the foundations for developing T-cell assays to monitor human beta cell antigen specific T cell responses in type 1 diabetes.