Divergent Phenotypes of Human Regulatory T Cells Expressing the Receptors TIGIT and CD226

J Immunol. 2015 Jul 1;195(1):145-55. doi: 10.4049/jimmunol.1402381. Epub 2015 May 20.


Regulatory T cells (Tregs) play a central role in counteracting inflammation and autoimmunity. A more complete understanding of cellular heterogeneity and the potential for lineage plasticity in human Treg subsets may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. To better elucidate human Treg subsets, we conducted direct transcriptional profiling of CD4(+)FOXP3(+)Helios(+) thymic-derived Tregs and CD4(+)FOXP3(+)Helios(-) T cells, followed by comparison with CD4(+)FOXP3(-)Helios(-) T conventional cells. These analyses revealed that the coinhibitory receptor T cell Ig and ITIM domain (TIGIT) was highly expressed on thymic-derived Tregs. TIGIT and the costimulatory factor CD226 bind the common ligand CD155. Thus, we analyzed the cellular distribution and suppressive activity of isolated subsets of CD4(+)CD25(+)CD127(lo/-) T cells expressing CD226 and/or TIGIT. We observed TIGIT is highly expressed and upregulated on Tregs after activation and in vitro expansion, and is associated with lineage stability and suppressive capacity. Conversely, the CD226(+)TIGIT(-) population was associated with reduced Treg purity and suppressive capacity after expansion, along with a marked increase in IL-10 and effector cytokine production. These studies provide additional markers to delineate functionally distinct Treg subsets that may help direct cellular therapies and provide important phenotypic markers for assessing the role of Tregs in health and disease.

Publication types

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

MeSH terms

  • Adult
  • Antigens, Differentiation, T-Lymphocyte / genetics
  • Antigens, Differentiation, T-Lymphocyte / immunology*
  • CD4 Antigens / genetics
  • CD4 Antigens / immunology
  • Cell Differentiation
  • Cell Lineage / immunology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Gene Expression Profiling
  • Humans
  • Ikaros Transcription Factor / genetics
  • Ikaros Transcription Factor / immunology
  • Immunophenotyping
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology
  • Ligands
  • Lymphocyte Activation
  • Middle Aged
  • Phenotype*
  • Primary Cell Culture
  • Protein Binding
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology*
  • Receptors, Virus / genetics
  • Receptors, Virus / immunology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • Transcriptome / immunology*


  • Antigens, Differentiation, T-Lymphocyte
  • CD226 antigen
  • CD4 Antigens
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IKZF2 protein, human
  • IL10 protein, human
  • Ligands
  • Receptors, Immunologic
  • Receptors, Virus
  • TIGIT protein, human
  • poliovirus receptor
  • Interleukin-10
  • Ikaros Transcription Factor

Associated data

  • GEO/GSE59786
  • GEO/GSE61834
  • GEO/GSE62015