# MerTK Mediated T Cell Suppression in the Pancreatic Islets During Type 1 Diabetes

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $445,134

## Abstract

PROJECT SUMMARY:
When type 1 diabetes (T1D) patients present with disease, their immune system has already destroyed most
of the beta cells in their pancreatic islets. Remaining insulin-producing islets may already be infiltrated with
leukocytes, but remaining beta cell mass is instrumental for maintaining blood glucose control, leading to fewer
diabetes-related complications. Therefore, controlling the immune response in the islets, particularly T cells, is
of paramount importance for preserving remaining insulin production and preventing T1D progression. Our
work has shown that the immune response in the islets is temporally regulated. Pathogenic T cell stimulation
within the islets occurs early in islet infiltration. However, as islet infiltration advances, T cell restimulation in the
islets is at least transiently suppressed, through an undefined mechanism. Our preliminary data depleting
CD11c+ cells indicate that CD11c+ cells are responsible for this suppression of T cell restimulation in the islets.
Islet CD11c+ cells have differing effects on T cells as islet infiltration progresses, suggesting that islet CD11c+
populations might differ over time. However, there is a gap in knowledge about the specific CD11c+ cell
subsets that are present in the islets over the course of islet infiltration, the role of each CD11c+ subset in
modulating T cell pathogenicity in the islets, and the mechanisms of CD11c+ cell-mediated T cell suppression
in the islets. We found an islet-infiltrating CD11c+ population that expresses MerTK. MerTK is a receptor
tyrosine kinase that mediates apoptotic cell uptake and that has previously been implicated in tolerizing T cells
during T1D in NOD mice. Strikingly, our preliminary data show that MerTK inhibition induced rapid T1D onset
in asymptomatic NOD mice with advanced islet infiltration. Based on these findings, we hypothesize that a
subset of islet-infiltrating CD11c+ cells suppress T cell restimulation and effector function in the islets via a
MerTK dependent mechanism. To test this hypothesis, we will address the following aims using a variety of
techniques including in vivo 2-photon microscopy, single cell RNA-seq, flow cytometry, and analysis of disease
progression. Aim 1: To determine the function of islet-infiltrating CD11c+ cells and of MerTK in suppressing T
cell pathogenicity within the islets. Aim 2: To identify islet CD11c+ subsets and determine mechanisms by
which CD11c+MerTK+ cells promote tolerance in the islets during T1D. Aim 3: To identify the mononuclear
phagocyte populations and MerTK expression in human islets during T1D progression and to determine
whether MerTK expression or function is altered in T1D. Understanding the mechanisms of T cell suppression
in the islets by addressing these aims could allow us to therapeutically reinforce these pathways to protect beta
cells mass, insulin production, and blood glucose control in autoantibody-positive pre-diabetic or new-onset
diabetic patients.

## Key facts

- **NIH application ID:** 10054623
- **Project number:** 7R01DK111733-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Rachel S Friedman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $445,134
- **Award type:** 7
- **Project period:** 2020-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054623

## Citation

> US National Institutes of Health, RePORTER application 10054623, MerTK Mediated T Cell Suppression in the Pancreatic Islets During Type 1 Diabetes (7R01DK111733-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10054623. Licensed CC0.

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