IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells

Eur J Immunol. 2007 Nov;37(11):3021-9. doi: 10.1002/eji.200737810.


Epstein-Barr virus-induced gene 3 (EBI3) and the p35 subunit of IL-12 have been reported to form a heterodimeric hematopoietin in human and mouse. We have constructed a heterodimeric protein covalently linking EBI3 and p35, to form a novel cytokine which we now call IL-35. The Fc fusion protein of IL-35 induced proliferation of murine CD4(+)CD25(+) and CD4(+)CD25(-) T cells when stimulated with immobilized anti-CD3 and anti-CD28 antibodies in vitro. The IL-35-expanded CD4(+)CD25(+) T cell population expressed Foxp3 and produced elevated levels of IL-10, whereas the IL-35-induced CD4(+)CD25(-) T cells produced IFN-gamma but not IL-4. The in vitro expanded CD4(+)CD25(+) T cells retained their suppressive functions against CD4(+)CD25(-) effector cells. Furthermore, when cultured with soluble anti-CD3 antibody and antigen-presenting cells, IL-35 suppressed the proliferation of CD4(+)CD25(-) effector cells. Moreover, IL-35 inhibited the differentiation of Th17 cells in vitro. In vivo, IL-35 effectively attenuated established collagen-induced arthritis in mice, with concomitant suppression of IL-17 production but enhanced IFN-gamma synthesis. Thus, IL-35 is a novel anti-inflammatory cytokine suppressing the immune response through the expansion of regulatory T cells and suppression of Th17 cell development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / immunology*
  • Blotting, Western
  • Cell Differentiation / immunology
  • Cell Proliferation
  • Humans
  • Interleukin-12 Subunit p35 / immunology
  • Interleukin-12 Subunit p35 / metabolism
  • Interleukins / biosynthesis*
  • Interleukins / immunology*
  • Interleukins / metabolism
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred DBA
  • Minor Histocompatibility Antigens
  • Recombinant Proteins / biosynthesis*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*


  • EBI3 protein, human
  • Interleukin-12 Subunit p35
  • Interleukins
  • Minor Histocompatibility Antigens
  • Recombinant Proteins