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Accelerated Type 1 Diabetes Induction in Mice by Adoptive Transfer of Diabetogenic CD4+ T Cells
Published on: May 6, 2013
Blimp-1 benefits gut-homing regulatory T cells by maintaining migration/suppressive function in autoimmune
Yi-Wen Tsai1, Yu-Wen Liu2, Chao-Yuan Hsu3
1Graduate Institute of Medical Sciences, National Defense Medical University, No. 161, Section 6, Min Chuan East Road, Neihu, Taipei, 114, Taiwan; Department of Family Medicine, Chang Gung Memorial Hospital, Linkou, No. 5, Fuxing St., Guishan Dist., Taoyuan City, 333, Taiwan; Department of Family Medicine, New Taipei Municipal Tucheng Hospital (Bulit and Operated by Chang Gung Medical Foundation), No. 6, Section 2, Jincheng Road, Tucheng District, New Taipei City, 236, Taiwan; School of Medicine, College of Medicine, Chang-Gung University, No. 259, Wenhua 1st Road, Guishan District, Taoyuan City, 333, Taiwan.
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).
