CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner

Eur J Immunol. 2013 Aug;43(8):2043-54. doi: 10.1002/eji.201243296. Epub 2013 Jul 3.


Treg cells are critical for the prevention of autoimmune diseases and are thus prime candidates for cell-based clinical therapy. However, human Treg cells are "plastic", and are able to produce IL-17 under inflammatory conditions. Here, we identify and characterize the human Treg subpopulation that can be induced to produce IL-17 and identify its mechanisms. We confirm that a subpopulation of human Treg cells produces IL-17 in vitro when activated in the presence of IL-1β, but not IL-6. "IL-17 potential" is restricted to population III (CD4(+) CD25(hi) CD127(lo) CD45RA(-) ) Treg cells expressing the natural killer cell marker CD161. We show that these cells are functionally as suppressive and have similar phenotypic/molecular characteristics to other subpopulations of Treg cells and retain their suppressive function following IL-17 induction. Importantly, we find that IL-17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL-17. Finally, we show that CD161(+) population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL-17-producing Treg-cell population at these sites. As IL-17 production from this Treg-cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary.

Keywords: Conversion; Human; Regulatory T (Treg) cells; STAT3; Th17.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • CD4 Antigens / biosynthesis
  • Cells, Cultured
  • Female
  • Forkhead Transcription Factors / biosynthesis
  • Humans
  • Interleukin-17 / biosynthesis*
  • Interleukin-1beta / metabolism
  • Interleukin-2 Receptor alpha Subunit / biosynthesis
  • Interleukin-6 / metabolism
  • Interleukin-7 Receptor alpha Subunit / biosynthesis
  • Leukocyte Common Antigens / biosynthesis
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • NK Cell Lectin-Like Receptor Subfamily B / immunology
  • NK Cell Lectin-Like Receptor Subfamily B / metabolism*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*


  • CD4 Antigens
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-17
  • Interleukin-1beta
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-6
  • Interleukin-7 Receptor alpha Subunit
  • NK Cell Lectin-Like Receptor Subfamily B
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Leukocyte Common Antigens