IL-6 controls susceptibility to helminth infection by impeding Th2 responsiveness and altering the Treg phenotype in vivo

IL-6 plays a pivotal role in favoring T-cell commitment toward a Th17 cell rather than Treg-cell phenotype, as established through in vitro model systems. We predicted that in the absence of IL-6, mice infected with the gastrointestinal helminth Heligmosomoides polygyrus would show reduced Th17-cell responses, but also enhanced Treg-cell activity and consequently greater susceptibility. Surprisingly, worm expulsion was markedly potentiated in IL-6-deficient mice, with significantly stronger adaptive Th2 responses in both IL-6−/− mice and BALB/c recipients of neutralizing anti-IL-6 monoclonal Ab. Although IL-6-deficient mice showed lower steady-state Th17-cell levels, IL-6-independent Th17-cell responses occurred during in vivo infection. We excluded the Th17 response as a factor in protection, as Ab neutralization did not modify immunity to H. polygyrus infection in BALB/c mice. Resistance did correlate with significant changes to the associated Treg-cell phenotype however, as IL-6-deficient mice displayed reduced expression of Foxp3, Helios, and GATA-3, and enhanced production of cytokines within the Treg-cell population. Administration of an anti-IL-2:IL-2 complex boosted Treg-cell proportions in vivo, reduced adaptive Th2 responses to WT levels, and fully restored susceptibility to H. polygyrus in IL-6-deficient mice. Thus, in vivo, IL-6 limits the Th2 response, modifies the Treg-cell phenotype, and promotes host susceptibility following helminth infection

Macrobiota — helminths as active participants and partners of the microbiota in host intestinal homeostasis

Important insights have recently been gained in our understanding of the intricate relationship in the intestinal milieu between the vertebrate host mucosal immune response, commensal bacteria, and helminths. Helminths are metazoan worms (macrobiota) and trigger immune responses that include potent regulatory components capable of controlling harmful inflammation, protecting barrier function and mitigating tissue damage. They can secrete a variety of products that directly affect immune regulatory function but they also have the capacity to influence the composition of microbiota, which can also then impact immune function. Conversely, changes in microbiota can affect susceptibility to helminth infection, indicating that crosstalk between these two disparate groups of endobiota can play an essential role in host intestinal immune function and homeostasis

Parasite immunomodulation and polymorphisms of the immune system

Parasites are accomplished evaders of host immunity. Their evasion strategies have shaped every facet of the immune system, driving diversity within gene families and immune gene polymorphisms within populations. New studies published recently in BMC Biology and Journal of Experimental Medicine document parasite-associated immunosuppression in natural populations and suggest that host genetic variants favoring resistance to parasites may be detrimental in the absence of infection

Regulation of immunity and allergy by helminth parasites

There is increasing interest in helminth parasite modulation of the immune system, both from the fundamental perspective of the “arms race” between host and parasite, and equally importantly, to understand if parasites offer new pathways to abate and control untoward immune responses in humans. This article reviews the epidemiological and experimental evidence for parasite down‐regulation of host immunity and immunopathology, in allergy and other immune disorders, and recent progress towards defining the mechanisms and molecular mediators which parasites exploit in order to modulate their host. Among these are novel products that interfere with epithelial cell alarmins, dendritic cell activation, macrophage function and T‐cell responsiveness through the promotion of an immunoregulatory environment. These modulatory effects assist parasites to establish and survive, while dampening immune reactivity to allergens, autoantigens and microbiome determinants

Immunology: the neuronal pathway to mucosal immunity

Type 2 immunity at mucosal surfaces is thought to be initiated by type 2 innate lymphoid cells. New studies report that these cells are themselves activated by the neuropeptide neuromedin U, produced by cholinergic neurons in the gut and in airways

Myeloid Cell Phenotypes in Susceptibility and Resistance to Helminth Parasite Infections

Many major tropical diseases are caused by long-lived helminth parasites that are able to survive by modulation of the host immune system, including the innate compartment of myeloid cells. In particular, dendritic cells and macrophages show markedly altered phenotypes during parasite infections. In addition, many specialized subsets such as eosinophils and basophils expand dramatically in response to these pathogens. The changes in phenotype and function, and their effects on both immunity to infection and reactivity to bystander antigens such as allergens, are discussed

Alarming dendritic cells for Th2 induction

There is an ever-increasing understanding of the mechanisms by which pathogens such as bacteria, viruses, and protozoa activate dendritic cells (DCs) to drive T helper type 1 (Th1) responses, but we know much less about how these cells elicit Th2 responses. This gap in our knowledge puts us at a distinct disadvantage in designing therapeutics for certain immune-mediated diseases. However, progress is being made with the identification of novel endogenous tissue factors that can enhance Th2 induction by DCs

MHC-II: A Mutual Support System for ILCs and T Cells?

Innate and adaptive immune cells form an ongoing partnership during an immune response. In this issue of Immunity, Oliphant et al. (2014) show that MHC class II-peptide presentation by group 2 innate lymphoid cells is needed for reciprocal regulation of both cell types, resulting in effective antihelminth immunity

Inflammatory bowel disease

Inflammatory bowel disease (IBD) is an immunological disorder, encompassing Crohn’s disease and ulcerative colitis, which are characterized by chronic intestinal inflammation targeted at harmless commensal bacteria and food antigens. Although the aetiology of IBD remains unclear, environmental factors in susceptible individuals appear to trigger immunological responses that inflame and damage tissues of the digestive tract. Prevalence of IBD is markedly higher in industrialized and affluent countries [1] (see Fig. 1). Evidence of a major underlying role for genetic predisposition to IBD raises the likelihood that the origins of disease and the susceptibility of the current human ‘immunome’ is the evolutionary consequence of marked and prolonged genetic selective pressure exerted by infectious pathogens [3]

Identifying novel candidates and configurations for human helminth vaccines

Introduction: Human infections with helminth worm parasites are extraordinarily prevalent across tropical and subtropical parts of the world, and control relies primarily on drugs that offer short-term suppression of infection. There is an urgent need for new vaccines that would confer long-lived immunity, protecting children in particular and minimizing community transmission. Areas covered: This article discusses the development of helminth vaccines, from the first successful veterinary vaccines that demonstrated the feasibility of inducing protective immunity to helminths, to more recent initiatives to test human helminth antigens. The field has focussed primarily on evaluating individual antigens that could constitute targets amenable to antibody attack to inhibit parasite establishment. In a new direction, vaccines employing extracellular vesicles released by helminths have also given exciting results. Expert opinion: Taking into account the complex life cycles and sophisticated immune evasion strategies of many helminths, a combination of antigens and approaches designed to target essential functional pathways of the parasite will be required to achieve a high level of protection in future anti-helminth vaccines