Mechanisms Underlying Antigen-Specific Tolerance of Stable and Convertible Th17 Cells During Suppression of Autoimmune Diabetes
- Xiaoxiao Wan1,
- F. Betul Guloglu1,2,
- Amie M. VanMorlan3,
- Linda M. Rowland1,
- Renu Jain1,4,
- Cara L. Haymaker1,5,
- Jason A. Cascio1,
- Mermagya Dhakal1,
- Christine M. Hoeman1,
- Danielle M. Tartar1 and
- Habib Zaghouani1,3⇓
- 1Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri
- 2Scientific and Technological Research Council of Turkey, Marmara Research Center, Genetic Engineering and Biotechnology Institute, Gebze, Kocaeli, Turkey
- 3Department of Child Health, University of Missouri School of Medicine, Columbia, Missouri
- 4Merck Research Laboratories, Palo Alto, California
- 5Department of Melanoma Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
- Corresponding author: Habib Zaghouani, .
Type 1 diabetes involves both T helper (Th)1 and Th17 cells. While the mechanisms underlying the control of Th1 cells are relatively well defined, those operating modulation of Th17 cells remain unknown. Moreover, given that Th17 cells are plastic and can drive disease as stable or convertible T cells, effective approaches to counter type 1 diabetes would have to alter Th17 function under both circumstances. Herein, we genetically incorporated the BDC2.5-reactive p79 mimotope into an Ig molecule, and the resulting Ig-p79 was used to investigate Th17 tolerance. Accordingly, diabetogenic BDC2.5 Th17 cells were transferred into NOD mice under convertible or stable conditions and their fate was evaluated upon induction of tolerance and disease suppression by Ig-p79. The findings show that convertible (Th17 to Th1) cells display downregulation of the chemokine (C-X-C motif) receptor 3 that was associated with diminished T-box transcription factor T-bet expression, retention in the spleen, and inhibition of trafficking to the pancreas. In contrast, stable Th17 cells downregulated orphan nuclear receptor ROR-γt but increased Fas ligand expression and died by apoptosis. Thus, the final signature transcription factor shapes the mechanism of tolerance in plastic Th17 cells. These findings suggest that effective strategies against type 1 diabetes will require regimens that could drive both mechanisms of tolerance to overcome the disease.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1723/-/DC1.
- Received December 9, 2011.
- Accepted March 14, 2012.
- © 2012 by the American Diabetes Association.
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