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

Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: 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 National Science and Technology Council, Taiwan (NSTC112-2320-B-400-026-MY3, NSTC113-2320-B-400-019-MY3); the Tri-Service General Hospital (TSGH-C02-112029, TSGH-C03-113037, TSGH-C01-114028, VTA112-T-1-1, VTA113-T-1-1); and the Chang Gung Memorial Hospital Research Projects (NMRPG2K0021, CMRPG2M0041, CMRPVVM0182, CORPVVN0131, CMRPG2I0071, CMRPG2I0072, CMRPG2I0073, CORPG3P0622).