# Galectin-3 exacerbates autoimmune diabetes by limiting regulatory T cell differentiation and function

## TL;DR

Galectin-3 worsens autoimmune diabetes by blocking regulatory T cells, and inhibiting it could help treat the disease.

## Contribution

This study reveals Galectin-3 as a new biomarker and therapeutic target for type 1 diabetes.

## Key findings

- Galectin-3 levels are elevated in T1D patients and their relatives, mainly from monocytes/macrophages.
- Blocking Galectin-3 protects against diabetes in NOD mice by restoring regulatory T cell function.
- Galectin-3 activates LAG3 to suppress MEK/ERK signaling, impairing Treg cell differentiation.

## Abstract

Galectin-3, a β-galactoside–binding lectin, has been implicated in several inflammatory and autoimmune diseases. However, the significance of circulating Galectin-3 in type 1 diabetes (T1D) remains unclear. Here, we report that compared to healthy controls, patients with T1D and their first-degree relatives (FDRs) exhibited significantly increased serum Galectin-3 levels primarily produced and secreted by monocytes/macrophages. Pharmacological inhibition (TD139) as well as knockout of Galectin-3 gene both attenuated Galectin-3–mediated suppression of regulatory T cells (Treg cells) and protected from insulitis and diabetes onset in NOD mice. Mechanistically, Galectin-3 bound to and activated lymphocyte activation gene 3 (LAG3), a receptor expressed on activated T cells, subsequently suppressing the MEK/ERK signaling pathway and thereby hindering Treg cell differentiation and function. In summary, our study identifies Galectin-3 as a potential biomarker for T1D and suggests that TD139 holds promise as a therapeutic candidate for patients with T1D and high serum Galectin-3 levels.

Galectin-3 activates LAG3 to inhibit Treg cell differentiation and function, thereby triggering immune imbalance and insulitis.