Matthew Bettini, Greg Delgoffe, Dario Vignali

Signaling by a Novel Cytokine Mediates Immune Suppression

An important mechanism of action of regulatory T (Treg) cells and other immunosuppressive cells is to secrete cytokines that have anti-inflammatory properties. Cytokines are signaling molecules that mediate cellular communication. Whereas the number of immunostimulatory cytokines that have been characterized thus far exceeds that of anti-inflammatory cytokines, the few anti-inflammatory cytokines that have been characterized possess potent immunosuppressive activities.

IL-35, a newly discovered immunosuppressive cytokine, belongs to the IL-12 family of cytokines that also includes IL-12, IL-23, and IL-27. IL-35 mediates two major biological functions by acting on target T cells: suppression of T-cell proliferation and conversion of naïve T cells into IL-35–producing induced Treg (iTr35) cells.

Until last year, the molecular components of the IL-35 receptor and its downstream signaling pathways remained undefined. In Nature Immunology, Dario A. A. Vignali, PhD (Immunology) and members of his laboratory published the molecular identity of this receptor. Unlike the receptors for the other members of the IL-12 family of cytokines, the IL-35 receptor is composed of either a heterodimer of two distinct cytokine receptor chains (IL-12Rβ2 and gp130) or a homodimer of each chain.

The researchers were surprised to learn that although either the IL-12Rβ2 or gp130 homodimer can induce IL-35–mediated suppression of T-cell proliferation, only the IL-12Rβ2–gp130 heterodimer can induce iTr35 cells.

In addition, the signaling pathways activated after ligation of the IL-35 receptor by IL-35 were equally surprising. Among the signal transducer and activator of transcription (STAT) family of transcription factors that transduce cytokine signaling, STAT1 and STAT4 are activated by the IL-35 receptor and are required for IL-35–mediated suppression of T-cell proliferation. Although STAT transcription factors typically function as homodimers, a novel STAT1–STAT4 heterodimer is essential for the induction of iTr35 cells and thus the anti-inflammatory program.

These findings reveal a previously unappreciated mode of cytokine signaling. As the IL-35–receptor chain IL-12Rβ2 has been linked to human autoimmune and inflammatory diseases, including type 1 diabetes and atopic dermatitis, and IL-35 production may be enhanced in the tumor microenvironment, the IL-35/IL-35–receptor axis represents a potential new target for therapeutic intervention of human disease.