Immune receptors, including T cell receptors (TCRs) on T cells and B cell receptors (BCRs) on B cells, are central to immune responses, mediating antigen recognition and tissue specificity. Characterizing the immune receptor repertoires during type 1 diabetes (T1D) progression provides key insights into the T and B cell populations contributing to disease pathogenesis. The overarching goal of this project is to identify and characterize the immune receptors expressed by T and B cells infiltrating the pancreas and islets at various stages of T1D.
Over the past decade, we have identified TCR sequences in the pancreas of stage 3 T1D donors (those requiring insulin therapy) and non-diabetic individuals. We found that only diabetic donors possess T cells recognizing both native and modified forms of (pre-pro)insulin, highlighting insulin and its derivertives as key targets in beta cell autoimmunity. These results underscore the crucial role of insulin and its processing forms as autoimmune targets in T1D. However, due to the low frequency of islet-specific T cells in the pancreas and the significant antigenic heterogeneity observed between individuals, further investigation is necessary to delineate the immune receptors involved in T1D.
Two critical questions remain: (1) What are the immune receptors and their target antigens expressed by T and B cells during the earlier stages of T1D? and (2) What are the phenotypic characteristics of T and B cells expressing islet-specific immune receptors?
To address these questions, we propose to:
- Identify immune receptors expressed by T and B cells in the pancreas of donors at T1D different stages and investigate their antigen specificity.
- Profile gene expression associated with immune receptor signatures in individual T and B cells from pancreatic lymph nodes.
Completion of this study will provide crucial insights into the antigen specificity required for the adaptive immune system in T1D development, and inform strategies for immunotherapy and biomarker development for T1D.