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

Research Opportunity
PhD, Master of Biomedical Science
Number of Master Places Available
1
Department
Medicine and Radiology
Location
St Vincent's Institute of Medical Research
Primary Supervisor Email Number Webpage
A/Prof Stuart Mannering smannering@svi.edu.au Personal web page
Co-supervisor Email Number Webpage
Dr Colleen Elso celso@svi.edu.au
Prof Helen Thomas hthomas@svi.edu.au

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.



Faculty Research Themes

Infection and Immunology

School Research Themes



Research Opportunities

PhD, Master of Biomedical Science
Students who are interested in joining this project will need to consider their elegibility as well as other requirements before contacting the supervisor of this research

Graduate Research application

Honours application

Key Contact

For further information about this research, please contact a supervisor.

Department

Medicine and Radiology

Research Node

St Vincent's Institute of Medical Research

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