# Mechanisms Underlying the Role of Interleukin-7 in Type 1 Diabetes

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $424,766

## Abstract

   
DESCRIPTION (provided by applicant):  Interleukin-7 (IL-7) is a cytokine with broad functionality in the immune system: it is critical for lymphocyte development and peripheral T cell survival. Recent evidence however indicates that polymorphisms in IL-7Rα are associated with increased risk for various autoimmune diseases and blocking IL-7/IL-7Rα interaction in mouse models of Type 1 Diabetes (T1D), Multiple Sclerosis, and Rheumatoid Arthritis has therapeutic benefit. Together, these studies strongly suggest that the IL-7/IL-7Rα pathway plays a critical role in the development of autoimmunity. We found that IL-7Rα blockade prevents and reverses autoimmune diabetes in non-obese diabetic (NOD) mice, which spontaneously develop a disease similar to human T1D. The main goal of this proposal is to understand the mechanisms underlying the role of IL-7/IL-7Rα in the pathogenesis of T1D as a basis for developing novel immunotherapies targeting the IL-7 pathway. The central hypothesis is that IL-7 promotes T1D by enabling autoreactive CD4+ T cells to escape critical regulatory mechanisms, resulting in compromised tissue tolerance. Increased access to IL-7 due to production of the cytokine in the pancreas and altered IL-7 signaling in autoreactive T cells are potential mechanisms underlying IL-7-driven autoimmunity. Therefore, we will perform an in-depth analysis in NOD mice of IL-7 production at the autoimmune site, and of the role of IL-7 receptor signaling in effector/memory T cells and Tregs.  In Specific Aim 1, we will investigate how IL-7 counteracts inhibitory receptor expression induced in autoreactive CD4+ T cells exposed to persistent islet self-antigens. The role of IL- 7Rα expression levels and distinct IL-7
signaling pathways in preventing regulation of islet- specific T cells in the pancreas will be determined using novel phosphoflow cytometry. In Specific Aim 2, we will investigate the role of IL-7Rα expression in pancreatic Tregs, using a novel conditional knockout mouse model allowing specific deletion of IL-7Rα in Foxp3+ Tregs. Impact on T1D development will be evaluated. In Specific Aim 3, we will characterize IL-7- producing cells in the pancreas during progressive autoimmune inflammation and we will identify the signals inducing pancreatic IL-7 expression, using novel IL-7/GFP knock-in reporter mice.  We have generated innovative mouse models to investigate how IL-7 drives autoimmune disease. Successful execution of the proposed experiments will provide critical knowledge to design novel strategies for therapeutic targeting of the IL-7/IL-7Rα pathway in T1D and, perhaps, other autoimmune conditions.

## Key facts

- **NIH application ID:** 9844940
- **Project number:** 5R01DK102911-05
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Hans Peter Dooms
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $424,766
- **Award type:** 5
- **Project period:** 2015-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844940

## Citation

> US National Institutes of Health, RePORTER application 9844940, Mechanisms Underlying the Role of Interleukin-7 in Type 1 Diabetes (5R01DK102911-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9844940. Licensed CC0.

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