Interleukin-35 induces regulatory B cells that suppress autoimmune disease

Nat Med. 2014 Jun;20(6):633-41. doi: 10.1038/nm.3554. Epub 2014 Apr 17.


Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adoptive Transfer / methods*
  • Animals
  • Autoimmune Diseases / drug therapy*
  • B-Lymphocytes, Regulatory / metabolism*
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • DNA Primers / genetics
  • Genetic Engineering
  • Immunoprecipitation
  • Interleukin-10 / metabolism
  • Interleukin-12 Receptor beta 2 Subunit / genetics
  • Interleukins / administration & dosage
  • Interleukins / genetics
  • Interleukins / metabolism
  • Interleukins / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Real-Time Polymerase Chain Reaction
  • Recombinant Proteins / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Statistics, Nonparametric
  • Uveitis / drug therapy*


  • DNA Primers
  • Interleukin-12 Receptor beta 2 Subunit
  • Interleukins
  • Recombinant Proteins
  • interleukin-35, mouse
  • Interleukin-10