Enhanced suppressor function of TIM-3+ FoxP3+ regulatory T cells

Eur J Immunol. 2014 Sep;44(9):2703-2711. doi: 10.1002/eji.201344392. Epub 2014 Jun 16.


T-cell immunoglobulin and mucin domain 3 (TIM-3) is an Ig-superfamily member expressed on IFN-γ-secreting Th1 and Tc1 cells and was identified as a negative regulator of immune tolerance. TIM-3 is expressed by a subset of activated CD4(+) T cells, and anti-CD3/anti-CD28 stimulation increases both the level of expression and the number of TIM-3(+) T cells. In mice, TIM-3 is constitutively expressed on natural regulatory T (Treg) cells and has been identified as a regulatory molecule of alloimmunity through its ability to modulate CD4(+) T-cell differentiation. Here, we examined TIM-3 expression on human Treg cells to determine its role in T-cell suppression. In contrast to mice, TIM-3 is not expressed on Treg cells ex vivo but is upregulated after activation. While TIM-3(+) Treg cells with increased gene expression of LAG3, CTLA4, and FOXP3 are highly efficient suppressors of effector T (Teff) cells, TIM-3(-) Treg cells poorly suppressed Th17 cells as compared with their suppression of Th1 cells; this decreased suppression ability was associated with decreased STAT-3 expression and phosphorylation and reduced gene expression of IL10, EBI3, GZMB, PRF1, IL1Rα, and CCR6. Thus, our results suggest that TIM-3 expression on Treg cells identifies a population highly effective in inhibiting pathogenic Th1- and Th17-cell responses.

Keywords: FoxP3; Regulatory T (Treg) cells; TIM-3; Th17.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • CTLA-4 Antigen / immunology
  • Cell Differentiation / immunology
  • Female
  • Forkhead Transcription Factors / immunology*
  • Gene Expression Regulation / immunology*
  • Granzymes / immunology
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / immunology
  • Interleukin-10 / immunology
  • Interleukins / immunology
  • Male
  • Membrane Proteins / immunology*
  • Mice
  • Minor Histocompatibility Antigens
  • Receptors, CCR6 / immunology
  • STAT3 Transcription Factor / immunology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / cytology
  • Th17 Cells / immunology*


  • Antigens, CD
  • CCR6 protein, human
  • CD223 antigen
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • EBI3 protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • IL10 protein, human
  • IL1RN protein, human
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukins
  • Membrane Proteins
  • Minor Histocompatibility Antigens
  • Receptors, CCR6
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Interleukin-10
  • GZMB protein, human
  • Granzymes