The immunoregulatory cytokine TGF-β is pleiotropic due to the near-ubiquitous expression of the TGF-β receptors TβRI and TβRII on diverse cell types. The helminth parasite Heligmosomoides polygyrus has convergently evolved a family of TGF-β mimics (TGMs) that bind both these receptors through domains 1–3 of a 5-domain protein. One member of this family, TGM4, differs from TGF-β in acting in a cell-specific manner, failing to stimulate fibroblasts, but activating SMAD phosphorylation in macrophages. Primarily through domains 4 and 5, TGM4 interacts with multiple co-receptors, including CD44, CD49d (integrin α4) and CD206, and can up- and downmodulate macrophage responses to IL-4 and lipopolysaccharide (LPS), respectively. The dependence of TGM4 on combinatorial interactions with co-receptors is due to a moderated affinity for TβRII that is more than 100-fold lower than for TGF-β. Thus the parasite has elaborated TGF-β receptor interactions to establish cell specificity through combinatorial cis-signalling, an innovation absent from the mammalian cytokine.