Helminth parasites defy immune exclusion through sophisticated evasion mechanisms, including activation of host immunosuppressive regulatory T (Treg) cells. The mouse parasite Heligmosomoides polygyrus can expand the host Treg population by secreting products that activate TGF-β signalling, but the identity of the active molecule is unknown. Here we identify an H. polygyrus TGF-β mimic (Hp-TGM) that replicates the biological and functional properties of TGF-β, including binding to mammalian TGF-β receptors and inducing mouse and human Foxp3+ Treg cells. Hp-TGM has no homology with mammalian TGF-β or other members of the TGF-β family, but is a member of the complement control protein superfamily. Thus, our data indicate that through convergent evolution, the parasite has acquired a protein with cytokine-like function that is able to exploit an endogenous pathway of immunoregulation in the host.

Modification of the innate immune cell environment has recently been recognized as a viable treatment strategy for reducing autoimmune disease pathology. MIS416 is a microparticulate immune response modifier that targets myeloid cells, activating cytosolic receptors NOD2 and TLR9, and has completed a phase 1b/2a trial for the treatment of secondary progressive multiple sclerosis. Using a mouse model of multiple sclerosis, we are investigating the pathways by which activation of TLR9 and NOD2 may modify the innate immune environment and the subsequent T cell-mediated autoimmune responses. We have found that MIS416 has profound effects on the Th subset balance by depressing antigen-specific Th1, Th17, and Th2 development. These effects coincided with an expansion of specific myeloid subpopulations and increased levels of MIS416-stimulated IFN-γ by splenocytes. Additionally, systemic IFN-γ serum levels were enhanced and correlated strongly with disease reduction, and the protective effect of MIS416 was abrogated in IFN-γ-deficient animals. Finally, treatment of secondary progressive MS patients with MIS416 similarly elevated the levels of IFN-γ and IFN-γ–associated proteins in the serum. Together, these studies demonstrate that administration of MIS416, which targets innate cells, reshapes autoimmune T cell responses and leads to a significant reduction in CNS inflammation and disease.

Summary Helminth parasites infect an alarmingly large proportion of the world's population, primarily within tropical regions, and their ability to down‐modulate host immunity is key to their persistence. Helminths have developed multiple mechanisms that induce a state of hyporesponsiveness or immune suppression within the host; of particular interest are mechanisms that drive the induction of regulatory T‐cells (Tregs). Helminths actively induce Tregs either directly by secreting factors, such as the TGF‐β mimic Hp‐ TGM, or indirectly by interacting with bystander cell types such as dendritic cells and macrophages that then induce Tregs. Expansion of Tregs not only enhances parasite survival but, in cases such as filarial infection, Tregs also play a role in preventing parasite‐associated pathologies. Furthermore, Tregs generated during helminth infection have been associated with suppression of bystander immunopathologies in a range of inflammatory conditions such as allergy and autoimmune disease. In this review, we discuss evidence from natural and experimental infections that point to the pathways and molecules involved in helminth Treg induction, and postulate how parasite‐derived molecules and/or Tregs might be applied as anti‐inflammatory therapies in the future.