# The Antigen Repertoire of CD4 T cells from Pancreatic Islets

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $446,132

## Abstract

Project Summary
Type 1 diabetes (T1D) is a tissue-specific autoimmune disorder. Strong genetic association with the HLA class
II gene locus suggests the importance of CD4 T cells in initiating and driving the disease process. We and others
have isolated T cells from the pancreas of T1D organ donors and identified T cell epitopes specific to insulin,
and its precursor preproinsulin, as well as fusion peptides. An important next step is to elucidate the phenotypes
of such islet-derived T cells in health and disease. Concurrently, the previous studies uncovered the fact that
antigens for the majority of T cells in the islets are still unknown, and we do not even know whether those T cells
are islet antigen-specific. Identifying antigen specificity of islet-CD4 T cells is critical to dissect disease
pathogenicity and heterogeneity to develop antigen-specific immunotherapy to halt disease progression using
appropriate antigens in a given individual. Therefore, the goal of this grant is to identify antigen specificity of CD4
T cells in the islets and link antigen-specific responses to T cell phenotypes.
Multiple lines of evidence suggest that there may be `common' or preferred CD4 T cell epitopes within subsets
of T1D patients. First, the vast majority of T1D patients have risk HLA class II alleles, and specific class II alleles
are associated with development of an initial islet autoantibody (e.g. insulin autoantibodies develop in those with
HLA-DR4, and glutamic acid decarboxylase-65 antibodies with HLA-DR3). Second, CD4 T cells having the same
antigen specificity (e.g. proinsulin peptides and hybrid insulin peptides) are detected in the pancreata from
multiple T1D organ donors, and the same reactivity is found in the blood of those with early stages of T1D.
Finally, CD4 T cells specific to these epitopes have an inflammatory phenotype in the blood of T1D patients
compared to non-diabetic controls. This leads us to hypothesize that islet autoimmunity is promoted and
regulated by CD4 T cells reacting to `common' antigens that are shared by T1D patients having specific HLA
class II molecules. We will determine the proportion of tissue-specific CD4 T cells in the islets (Aim 1) and seek
to identify epitopes targeted by CD4 T cells in the islets of T1D organ donors (Aim 2). Furthermore, we will
determine the molecular phenotype of islet antigen-specific T cells in the pancreatic lymph nodes and spleen of
organ donors with and without T1D (Aim 3). The successful completion of this proposal will: (1) identify antigens
and epitopes targeted by CD4 T cells from pancreatic islets across the stages of T1D development and (2)
elucidate the molecular phenotype and features that render these T cells pathogenic. Thus, these studies will
enhance our understanding of human T1D pathogenesis, dissect disease heterogeneity, and aid in improving
the design of clinical trials evaluating antigen-specific immunotherapy for diabetes prevention.

## Key facts

- **NIH application ID:** 10873167
- **Project number:** 5R01DK133457-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Maki Nakayama
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $446,132
- **Award type:** 5
- **Project period:** 2022-09-10 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873167

## Citation

> US National Institutes of Health, RePORTER application 10873167, The Antigen Repertoire of CD4 T cells from Pancreatic Islets (5R01DK133457-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10873167. Licensed CC0.

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