Development of autoreactive diabetogenic T cells in the thymus of NOD mice

Hyokjoon Kwon, Hee Sook Jun, Yang Yang, Conchi Mora, Sanjeev Mariathasan, Pamela S. Ohashi, Richard A. Flavell, Ji Won Yoon

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Type 1 diabetes results from destruction of pancreatic β cells by β cell-specific autoreactive T cells in the nonobese diabetic (NOD) mouse. Defects in thymic negative selection are thought to result in failure to delete potential β cell-reactive T cells, contributing to the development of autoimmune diabetes. We investigated this possibility by comparing the deletion profile of double-positive (DP) thymocytes in NOD mice with diabetes-resistant strains of mice after anti-CD3 Ab treatment to trigger the TCR-mediated signaling pathway. We found that immature NOD CD4+CD8+ DP thymocytes have a lower activation threshold than C57BL/6 and Balb/c thymocytes. This was confirmed by showing that NOD DP thymocytes have a higher level of ERK and JNK phosphorylation. The low activation threshold of immature thymocytes resulted in rapid deletion of strongly activated immature DP thymocytes by negative selection, whereas weakly activated immature thymocytes differentiated more efficiently into CD69+CD3high DP thymocytes by positive selection. SP thymocytes, particularly CD4-CD8+ T cells that were efficiently generated from activated DP thymocytes, could induce severe insulitis and diabetes in NOD.scid mice. We conclude that the development of autoreactive diabetogenic T cells results from inordinate positive selection due to the low activation threshold of DP thymocytes in NOD mice.

Original languageEnglish (US)
Pages (from-to)11-23
Number of pages13
JournalJournal of Autoimmunity
Volume24
Issue number1
DOIs
StatePublished - Feb 2005

Keywords

  • Autoimmune diabetes
  • Cell differentiation
  • Cell-mediated immunity
  • Cytotoxic T lymphocytes
  • Immune tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Kwon, H., Jun, H. S., Yang, Y., Mora, C., Mariathasan, S., Ohashi, P. S., Flavell, R. A., & Yoon, J. W. (2005). Development of autoreactive diabetogenic T cells in the thymus of NOD mice. Journal of Autoimmunity, 24(1), 11-23. https://doi.org/10.1016/j.jaut.2004.10.002