Role of IFN-gamma in Induction of Foxp3 and Conversion of CD4+ CD25- T Cells to CD4+ Tregs

J Clin Invest. 2006 Sep;116(9):2434-41. doi: 10.1172/JCI25826. Epub 2006 Aug 10.

Abstract

IFN-gamma is an important Th1 proinflammatory cytokine and has a paradoxical effect on EAE in which disease susceptibility is unexpectedly heightened in IFN-gamma-deficient mice. In this study, we provide what we believe is new evidence indicating that IFN-gamma is critically required for the conversion of CD4+ CD25- T cells to CD4+ Tregs during EAE. In our study, the added severity of EAE in IFN-gamma knockout mice was directly associated with altered encephalitogenic T cell responses, which correlated with reduced frequency and function of CD4+ CD25+ Foxp3+ Tregs when compared with those of WT mice. It was demonstrated in both human and mouse systems that in vitro IFN-gamma treatment of CD4+ CD25- T cells led to conversion of CD4+ Tregs as characterized by increased expression of Foxp3 and enhanced regulatory function. Mouse CD4+ CD25- T cells, when treated in vitro with IFN-gamma, acquired marked regulatory properties as evidenced by suppression of EAE by adoptive transfer. These findings have important implications for the understanding of the complex role of IFN-gamma in both induction and self regulation of inflammatory processes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Brain / immunology
  • CD4 Antigens / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Forkhead Transcription Factors / genetics*
  • Interferon-gamma / deficiency
  • Interferon-gamma / genetics
  • Interferon-gamma / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Myelin Proteins
  • Myelin-Associated Glycoprotein / genetics
  • Myelin-Associated Glycoprotein / immunology
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments / chemistry
  • Polymerase Chain Reaction
  • Receptors, Interleukin-2 / immunology*
  • Spinal Cord / immunology
  • T-Lymphocytes / immunology*

Substances

  • CD4 Antigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • MOG protein, human
  • Mog protein, mouse
  • Myelin Proteins
  • Myelin-Associated Glycoprotein
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Receptors, Interleukin-2
  • Interferon-gamma