1. Department of Immunology,
2. Animal Resources Center, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
3. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
4. eBioscience, San Diego, California 92121, USA

Correspondence to: Dario A. A. Vignali¹ Correspondence and requests for materials should be addressed to D.A.A.V. (Email: dario.vignali@stjude.org).

Abstract

Regulatory T (T_reg) cells are a critical sub-population of CD4⁺ T cells that are essential for maintaining self tolerance and preventing autoimmunity^{1, 2}, for limiting chronic inflammatory diseases, such as asthma and inflammatory bowel disease^{3, 4}, and for regulating homeostatic lymphocyte expansion⁵. However, they also suppress natural immune responses to parasites⁶ and viruses⁷ as well as anti-tumour immunity induced by therapeutic vaccines⁸. Although the manipulation of T_reg function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. Here we demonstrate that Epstein-Barr-virus-induced gene 3 (Ebi3, which encodes IL-27) and interleukin-12 alpha (Il12a, which encodes IL-12/p35) are highly expressed by mouse Foxp3⁺ (forkhead box P3) T_reg cells but not by resting or activated effector CD4⁺ T (T_eff) cells, and that an Ebi3–IL-12 heterodimer is constitutively secreted by T_reg but not T_eff cells. Both Ebi3 and Il12a messenger RNA are markedly upregulated in T_reg cells co-cultured with T_eff cells, thereby boosting Ebi3 and IL-12 production in trans. T_reg-cell restriction of this cytokine occurs because Ebi3 is a downstream target of Foxp3, a transcription factor that is required for T_reg-cell development and function. Ebi3^–/– and Il12a^–/– T_reg cells have significantly reduced regulatory activity in vitro and fail to control homeostatic proliferation and to cure inflammatory bowel disease in vivo. Because these phenotypic characteristics are distinct from those of other IL-12 family members, this novel Ebi3–IL-12 heterodimeric cytokine has been designated interleukin-35 (IL-35). Ectopic expression of IL-35 confers regulatory activity on naive T cells, whereas recombinant IL-35 suppresses T-cell proliferation. Taken together, these data identify IL-35 as a novel inhibitory cytokine that may be specifically produced by T_reg cells and is required for maximal suppressive activity.

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