Mechanisms underlying antigen-specific tolerance of stable and convertible Th17 cells during suppression of autoimmune diabetes

Xiaoxiao Wan, F. Betul Guloglu, Amie M. VanMorlan, Linda M. Rowland, Renu Jain, Cara L. Haymaker, Jason A. Cascio, Mermagya Dhakal, Christine M. Hoeman, Danielle Tartar, Habib Zaghouani

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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-gt 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.

Original languageEnglish (US)
Pages (from-to)2054-2065
Number of pages12
JournalDiabetes
Volume61
Issue number8
DOIs
StatePublished - Aug 1 2012
Externally publishedYes

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Th17 Cells
Type 1 Diabetes Mellitus
Antigens
Th1 Cells
Plastics
CXCR3 Receptors
Down-Regulation
Orphan Nuclear Receptors
Inbred NOD Mouse
Fas Ligand Protein
Pancreas
Transcription Factors
Spleen
Apoptosis
T-Lymphocytes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Wan, X., Guloglu, F. B., VanMorlan, A. M., Rowland, L. M., Jain, R., Haymaker, C. L., ... Zaghouani, H. (2012). Mechanisms underlying antigen-specific tolerance of stable and convertible Th17 cells during suppression of autoimmune diabetes. Diabetes, 61(8), 2054-2065. https://doi.org/10.2337/db11-1723

Mechanisms underlying antigen-specific tolerance of stable and convertible Th17 cells during suppression of autoimmune diabetes. / Wan, Xiaoxiao; Guloglu, F. Betul; VanMorlan, Amie M.; Rowland, Linda M.; Jain, Renu; Haymaker, Cara L.; Cascio, Jason A.; Dhakal, Mermagya; Hoeman, Christine M.; Tartar, Danielle; Zaghouani, Habib.

In: Diabetes, Vol. 61, No. 8, 01.08.2012, p. 2054-2065.

Research output: Contribution to journalArticle

Wan, X, Guloglu, FB, VanMorlan, AM, Rowland, LM, Jain, R, Haymaker, CL, Cascio, JA, Dhakal, M, Hoeman, CM, Tartar, D & Zaghouani, H 2012, 'Mechanisms underlying antigen-specific tolerance of stable and convertible Th17 cells during suppression of autoimmune diabetes', Diabetes, vol. 61, no. 8, pp. 2054-2065. https://doi.org/10.2337/db11-1723
Wan, Xiaoxiao ; Guloglu, F. Betul ; VanMorlan, Amie M. ; Rowland, Linda M. ; Jain, Renu ; Haymaker, Cara L. ; Cascio, Jason A. ; Dhakal, Mermagya ; Hoeman, Christine M. ; Tartar, Danielle ; Zaghouani, Habib. / Mechanisms underlying antigen-specific tolerance of stable and convertible Th17 cells during suppression of autoimmune diabetes. In: Diabetes. 2012 ; Vol. 61, No. 8. pp. 2054-2065.
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