Hybrid Insulin Peptides are Recognized by Human T Cells in the Context of DRB1*04:01
This week we profile a recent publication in Diabetes from the laboratory of
Dr. Eddie James (pictured) at Benaroya Research Institute at Virginia Mason.
Can you provide a brief overview of your lab’s current research focus?
Our research is focused on understanding the selection, activation and expansion of an autoreactive T cell repertoire in autoimmunity. We utilize tools such as HLA tetramers to predict and validate epitopes within candidate antigens and to directly identify and characterize antigen-specific CD4+ and CD8+ T cells. The lab’s studies currently focus on type 1 diabetes and rheumatoid arthritis. The overarching goal of our research is to develop an increasingly in- depth knowledge of autoreactive T cell responses by examining the characteristics of epitope specific cells through robust multi-parameter assays and also at the single cell level. We seek to leverage that knowledge to develop clinically meaningful biomarkers and to reveal potential new avenues for therapy.
What is the significance of the findings in this publication?
This paper is based on collaborative work with Drs. Katie Haskins and Thomas Delong from the University of Colorado. The work focuses on a relatively new way that immune responses against pancreatic beta cells can be triggered. Beta cells are responsible for releasing insulin in response to elevated blood glucose. During this release, our collaborators observed that insulin secretory granules also contain non-genetically encoded hybrid peptides, formed by the fusion of fragments from pairs of unrelated proteins. These hybrids are perceived as foreign by immune cells and appear to elicit strong recognition by immune cells. We went on to show that T cells capable of recognizing these hybrids can be directly detected in the blood of patients who have type 1 diabetes, exhibit some of the same functional traits as virus specific T cells, and are capable of directly recognizing beta cells. In total this suggests that hybrid peptides specific T cells perceive beta cells as though they are infected with a pathogen.
What are the next steps for this research?
One interesting finding that we would like to follow up on is that some patients appear to have much higher numbers of T cells capable of recognizing hybrid peptides than others. A post-study analysis revealed two factors that differentiated subjects with high or low numbers: their age and the presence or absence of insulin autoantibodies. We are very interested in following up on those findings to determine why age might matter and whether there is a direct link between insulin autoantibodies and T cell responses to hybrid peptides.
This work was funded by:
Our work was supported by the Juvenile Diabetes Research Foundation and the National Institutes of Health.