# Blimp-1 benefits gut-homing regulatory T cells by maintaining migration/suppressive function in autoimmune diabetes-prone mice

## TL;DR

This study explores how Blimp-1 helps gut-homing regulatory T cells in mice prone to autoimmune diabetes, potentially offering new treatment approaches.

## Contribution

The study identifies Blimp-1's role in maintaining gut-homing Treg function and introduces Pep-based TCR signaling manipulation as a novel therapeutic strategy.

## Key findings

- Blimp-1-deficient NOD mice show more severe colitis and impaired gut-homing Treg function.
- Pep overexpression reverses colitis and restores Treg suppressive function in Blimp-1-deficient mice.
- T1D patients have a higher risk of inflammatory bowel disease, suggesting a gut–pancreas axis in disease development.

## Abstract

Genome-wide association studies (GWAS) have shown that Crohn's disease (CD) and type 1 diabetes (T1D) are the top 2 diseases with the highest genetic risk variants and share several susceptible loci. Since both CD and T1D are T cell-mediated diseases, we hypothesise a mechanistic linkage between T-cell homeostasis and a gut–pancreas axis that differentially regulates the immunopathogenesis and development between CD and T1D.

Using data for 1 million people from a 16-year nationwide population-based databank in Taiwan, we unraveled a higher risk of prevalent inflammatory bowel disease in T1D patients. This observation is supported by our model of T-cell-specific B-lymphocyte-induced maturation protein 1 (Blimp-1) deficiency-induced colitis, in which more severe colitogenesis was observed in diabetes-prone non-obese diabetic (NOD) mice than in non-diabetes-prone C57BL/6 mice.

Mechanistic investigations revealed that, compared with Tregs in C57BL/6 background, those in Blimp-1-deficient NOD mice exhibited decreased suppressive function, increased TCR signaling strength and impaired intestinal migration, particularly for gut-homing Th17-like Tregs. Strikingly, transgenic augmentation of PEST domain-enriched tyrosine phosphatase (Pep) to downregulate TCR signaling strength reversed exacerbated colitis and increased disease-free percentage of Blimp-1-deficient NOD mice. Adoptive transfer experiments further supported that Pep overexpression restored suppressive function of fragilized Tregs in Blimp-1-deficient NOD mice.

Our results demonstrate that Blimp-1 sustains the suppressive function of gut-homing Tregs and that Pep-based TCR signaling manipulation may serve as a therapeutic target in autoimmune diseases.

This study was funded by the Ministry of Science and Technology, Taiwan (MOST109-2320-B-400-018-MY3, MOST110-2320-B-400-011-MY3, MOST109-2314-B-182A-149); the 10.13039/100020595National Science and Technology Council, Taiwan (NSTC112-2320-B-400-026-MY3, NSTC113-2320-B-400-019-MY3); the 10.13039/501100010425Tri-Service General Hospital (TSGH-C02-112029, TSGH-C03-113037, TSGH-C01-114028, VTA112-T-1-1, VTA113-T-1-1); and the 10.13039/100012553Chang Gung Memorial Hospital Research Projects (NMRPG2K0021, CMRPG2M0041, CMRPVVM0182, CORPVVN0131, CMRPG2I0071, CMRPG2I0072, CMRPG2I0073, CORPG3P0622).