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NIH grant 1R01DK148774-01: The HLA Class I Immunopeptidome of Primary Islets in Health and Disease
Institute: {'code': 'DK', 'abbreviation': 'NIDDK', 'name': 'National Institute of Diabetes and Digestive and Kidney Diseases', 'admin_org_id': '12500020', 'admin_funding_url': ''}. PI: Teresa P DiLorenzo. Award: $636766.
Start: 2026-08-27T00:00:00.
ABSTRACT
The presentation of beta cell antigen-derived peptides by HLA class I molecules triggers CD8⁺ T cell
responses that contribute substantially to beta cell loss in type 1 diabetes (T1D). Islet-reactive CD8+ T cells
represent promising targets for immune intervention and monitoring strategies, rendering knowledge of their
cognate epitopes of prime importance. The HLA class I-bound peptides of human islets, known as the islet
immunopeptidome, is the collection of peptides with the potential to be recognized by CD8+ T cells contributing
to beta cell demise. Despite its importance, knowledge of the HLA class I immunopeptidome of primary islets is
severely limited. In particular, studies of the islet immunopeptidome of the T1D-predisposing allotypes HLA-
B*39:06 and A*24:02 are essentially non-existent. In Aim 1, we will characterize the constitutive HLA class I
immunopeptidome of primary human islets, with an emphasis on T1D susceptibility allotypes. Though rarely
studied due to the low basal levels of HLA expression, the constitutive islet immunopeptidome will provide
essential information for the selection of candidate T cell epitopes and a starting point to explore how the
immunopeptidome changes with disease. T1D is characterized by immune cell infiltration, an inflammatory
microenvironment, and an upregulation of HLA class I expression. In Aim 2, we will explore the inflammatory
islet immunopeptidome using islets from donors with T1D, a virtually unexplored area of investigation. As a
complementary strategy, islets from healthy donors cultured in the absence or presence of inflammatory
cytokines will allow a comparison of the constitutive and inflammatory islet immunopeptidomes of matched
samples. In Aim 3, we will evaluate candidate T cell epitopes identified from the islet immunopeptidome for
recognition by blood and islet-derived CD8+ T cells from patients with T1D. Recognition by CD8+ T cells derived
from the islets of donors with T1D will suggest epitopes with likely disease relevance. Functional CD8+ T cell
responses detected in peripheral blood will reveal epitopes having promise as immune monitoring tools. In Aim
4, we will uncover changes in the islet immunopeptidome with disease progression using our newly developed
double HLA-transgenic NOD mouse model of T1D that expresses two T1D-predisposing HLA class I allotypes.
The HLA class I immunopeptidome of islets from young, healthy mice will reveal potential targets of pathogenic
CD8+ T cells during the earliest stages of T cell infiltration and insulitis. The islet immunopeptidome of
hyperglycemic mice will suggest candidate T cell epitopes and therapeutic targets important during the
hyperglycemic stage of the disease. Our project will provide fundamental knowledge that will contribute to our
understanding of T1D pathogenesis and allow realization of the full potential of CD8+ T cells as targets for
immune intervention strategies and disease biomarkers. Our compelling preliminary studies support the
feasibility of our proposed work.document fetched 2026-09-06 02:47