# Shaping diabetogenic T cells by IL-27 in type 1 diabetes

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $371,608

## Abstract

PROJECT SUMMARY
Type 1 diabetes (T1D) is a life-long disease requiring daily injections of exogenous insulin. The incidence of
T1D has been increasing worldwide in recent decades. Genetic susceptibility and environmental factors
interactively contribute to T1D development. Human genetic studies have identified more than 50 loci
significantly linked to T1D. However, our knowledge of the underlying genes within these regions that
independently or cooperatively influence cellular processes leading to the destruction of insulin producing
pancreatic beta-cells is incomplete. To fill this gap, we used nuclease based approaches to target the murine
orthologs of human T1D candidate genes directly in nonobese diabetic (NOD) mice to seek functional
evidence of their roles in diabetes development. In this effort, we discovered that Il27 is essential for diabetes
development in NOD mice. Both CD4 and CD8 T cells are required for T1D development. How beta-cell
autoreactive T cells are activated, accumulate, and maintain their effector function during T1D progression has
not been fully defined. In this application we will determine the mechanisms by which IL-27 impacts T1D
through its direct effects on T cells. IL-27 exerts diverse immunological functions by binding to its receptors
(IL-27Ra and gp130 heterodimers) expressed on many immune cells, including macrophages, dendritic cells
(DCs), B cells, and T cells. We showed here that both NOD.Il27-/- and NOD.Il27ra-/- mice, respectively
lacking IL-27 and its receptor, were completely resistant to diabetes, indicating a critical role of IL-27 signaling
in T1D development. Our studies also demonstrated that IL-27 produced by macrophages and/or DCs was
sufficient to drive T1D but their responses to IL-27 were not important for diabetes development. Total T cells
isolated from NOD and NOD.Il27-/- mice were similarly diabetogenic when transferred into IL-27-sufficient
NOD.Rag1-/- recipients. Thus, β-cell autoreactive T cells are present in NOD.Il27-/- mice, but their pathogenic
activity cannot be induced or sustained in the absence of IL-27. In contrast, total T cells isolated from
NOD.Il27ra-/- mice did not induce T1D in NOD.Rag1-/- recipients, indicating that direct IL-27 signaling in T
cells promotes diabetes development. Using a mixed CD4 and CD8 T cell transfer approach, we further
demonstrated that IL-27 signaling in both CD4 and CD8 T cells is important for T1D progression. One
important diabetogenic activity of CD4 T cells is to provide help to autoreactive CD8 T cells that directly
recognize and kill insulin-producing beta-cells. Therefore, we hypothesize that IL-27 is important for the
accumulation and sustained effector function of beta-cell autoreactive CD8 T cells by directly acting on them
and indirectly through enhancing the helper function of CD4 T cells. We propose the following aims to test this
hypothesis. (1) To identify the mechanisms by which IL-27 intrinsically promotes beta-cell autoreactive ...

## Key facts

- **NIH application ID:** 10000910
- **Project number:** 5R01DK121747-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Yi-Guang Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,608
- **Award type:** 5
- **Project period:** 2019-08-22 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000910

## Citation

> US National Institutes of Health, RePORTER application 10000910, Shaping diabetogenic T cells by IL-27 in type 1 diabetes (5R01DK121747-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000910. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*