IL-4 induces a suppressive IL-10-producing CD8+ T cell population via a Cdkn2a-dependent mechanism

J Leukoc Biol. 2013 Dec;94(6):1103-12. doi: 10.1189/jlb.0213064. Epub 2013 Jun 14.


CD8(+) T cells play an important role in immune regulation and effective immune responses against tumor cells, viral infection, and intracellular pathogens. In this report, using tiger or 10BiT mice, we defined a population of IL-10-producing CD8(+) T cells that were induced by IL-4. These IL-10(+)CD8(+) T cells possessed a strong inhibitory effect on the CD4(+) T cell proliferation in an IL-10-dependent and cell contact-dependent fashion. In comparison with IL-10(-)CD8(+) T cells, IL-10(+)CD8(+) T cells expressed an array of Th2-like cytokines (IL-4, IL-5), perforin, and granzymes, as well as the cell cycle regulatory protein Cdkn2a. Interestingly, knockdown of cdkn2a using siRNA reduced IL-4-induced IL-10 production significantly. Furthermore, CD8(+) T cells from Cdkn2a(-/-) mice produced a significantly lower amount of IL-10, and the effect was limited to CD8(+) T cells but not observed in CD4(+) T cells and APCs. Finally, IL-10(+)CD8(+) T cells played a protective role in the TNBS-induced murine colitis model, indicating a critical role of this population of CD8(+) T cells in regulatory immune responses. Taken together, we have defined a population of IL-10-producing CD8(+) Tregs induced by IL-4 and mediated by Cdkn2a.

Keywords: differentiation; suppression; transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Colitis / chemically induced
  • Colitis / genetics
  • Colitis / immunology
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / immunology*
  • Disease Models, Animal
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology*
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology*
  • Interleukin-5 / genetics
  • Interleukin-5 / immunology
  • Mice
  • Mice, Knockout
  • Th2 Cells / immunology


  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • IL10 protein, mouse
  • Interleukin-5
  • Interleukin-10
  • Interleukin-4