Regulatory T cells in parasite infections: susceptibility, specificity and specialisation.

Regulatory T cells (Tregs) are essential to control immune system responses to innocuous self-specificities, intestinal and environmental antigens. However, they may also interfere with immunity to parasites, particularly in chronic infection. Susceptibility to many parasite infections is, to a greater or lesser extent, controlled by Tregs, but often they play a more prominent role in moderating the immunopathological consequences of parasitism, and dampening bystander reactions in an antigen-nonspecific manner. More recently, Treg subtypes have been defined which may preferentially act in different contexts; we also discuss the degree to which this specialisation is now being mapped onto how Tregs maintain the delicate balance between tolerance, immunity, and pathology in infection.

Suppression of airway allergic eosinophilia by Hp-TGM, a helminth mimic of TGF-ß.

Type 2-high asthma is a chronic inflammatory disease of the airways which is increasingly prevalent in countries where helminth parasite infections are rare, and characterized by T helper 2 (Th2)-dependent accumulation of eosinophils in the lungs. Regulatory cytokines such as TGF-ß can restrain inflammatory reactions, dampen allergic Th2 responses, and control eosinophil activation. The murine helminth parasite Heligmosomoides polygyrus releases a TGF-ß mimic (Hp-TGM) that replicates the biological and functional properties of TGF-ß despite bearing no structural similarity to the mammalian protein. Here, we investigated if Hp-TGM could alleviate allergic airway inflammation in mice exposed to Alternaria alternata allergen, house dust mite (HDM) extract or alum-adjuvanted ovalbumin protein (OVA). Intranasal administration of Hp-TGM during Alternaria exposure sharply reduced airway and lung tissue eosinophilia along with bronchoalveolar lavage fluid IL-5 and lung IL-33 cytokine levels at 24 h. The protective effect of Hp-TGM on airway eosinophilia was also obtained in the longer T-cell mediated models of HDM or OVA sensitisation with significant inhibition of eotaxin-1, IL-4 and IL-13 responses depending on the model and time-point. Hp-TGM was also protective when administered parenterally either when given at the time of allergic sensitisation or during airway allergen challenge. This project has taken the first steps in identifying the role of Hp-TGM in allergic asthma and highlighted its ability to control lung inflammation and allergic pathology. Future research will investigate the mode of action of Hp-TGM against airway allergic eosinophilia, and further explore its potential to be developed as a biotherapeutic in allergic asthma.

Regulatory T-cells in helminth infection: induction, function and therapeutic potential.

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-ß 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.