IL-27 influences the ratio of conventional T cells (T_CONV) to Treg populations during GVHD. (A) During acute GVHD pathogenesis, IL-27 receptor activation induces STAT1/STAT3 signaling, which in turn promotes Tbet transcription factor expression and downstream effector function, including both interferon-γ (IFN-γ) and IL-10 secretion. The shift toward T_CONV cells during acute GVHD is further exacerbated by a direct inhibitory effect of IL-27 on Treg cell in vivo stability. (B) Therapeutic mAb blockade of IL-27 reduces acute GVHD by limiting Th1- and Tc1-type T_CONV cells, including a reduction in IFN-γ and IL-10 secretion; in reciprocal fashion, anti–IL-27 therapy led to a dramatic increase in inducible Treg cells with preserved IL-10 secretion. Professional illustration by Patrick Lane, ScEYEnce Studios.