Diversity and dialogue in immunity to helminths

Key Points

  • Infection with large metazoan parasites (helminths) typically induces a type 2 immune response. Redundancy within the immune system, as well as extensive dialogue between cells of the immune system and non-immune cells, generates enormous complexity.

  • The central player in type 2 immunity is the CD4+ T helper 2 (TH2) cell, which produces a broad range of cytokines, including interleukin-4 (IL-4) and IL-13, which act on target cells expressing the IL-4 receptor α-chain. Target cells include most cells of the immune system but also local tissue cells such as epithelial cells that line mucosal surfaces.

  • Cells of the innate immune system, such as the recently described 'innate helper cells', can also produce type 2 cytokines. These cells function as effectors during the early stages of infection, but additionally create an environment that favours the induction of TH2-type responses.

  • TH2-type responses are initiated by alarm signals from epithelial cells, as well as by specific recognition of helminth products. A strict requirement for dendritic cells in this process has been established.

  • In addition to killing or expelling helminth parasites, type 2 immune responses contribute to rapid tissue repair, and this sometimes leads to fibrosis-related pathology. Many facets of type 2 immunity are consistent with evolutionary origins in wound-healing pathways, a reflection of the capacity of helminth parasites to damage tissue through migration and feeding.

  • T cell dynamics change over time, and TH2-type responses often decline during chronic helminth infection. Regulatory pathways, including regulatory T cells, restrain pathology and immune responses during infection, and some helminths are able to actively induce the expansion of regulatory populations.

  • Because mammals evolved in the presence of chronic infection, their immune systems may have compensated for the immune dampening effects of helminths. If so, over-reactive responses to innocuous antigens in the absence of infection may contribute to autoimmune disease and allergy.

Abstract

The vertebrate immune system has evolved in concert with a broad range of infectious agents, including ubiquitous helminth (worm) parasites. The constant pressure of helminth infections has been a powerful force in shaping not only how immunity is initiated and maintained, but also how the body self-regulates and controls untoward immune responses to minimize overall harm. In this Review, we discuss recent advances in defining the immune cell types and molecules that are mobilized in response to helminth infection. Finally, we more broadly consider how these immunological players are blended and regulated in order to accommodate persistent infection or to mount a vigorous protective response and achieve sterile immunity.

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Figure 1: IL-4Rα is at the centre of type 2 immunity.
Figure 2: TH2-type effector mechanisms in immunity to helminths.
Figure 3: Type 2 immunity in the repair of parasite-induced damage.
Figure 4: Homeostasis and tolerance in helminth infections.
Figure 5: Evolution of immune responsiveness to compensate for parasite immunosuppression.

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Acknowledgements

The authors gratefully acknowledge funding support from Asthma UK, the UK Medical Research Council and the Wellcome Trust (to J.E.A. and R.M.M.), the European Commission (to J.E.A.) and the American Asthma Foundation (to R.M.M.). We thank the members of our laboratories for the extensive discussions and interactions that have helped develop many of the concepts in this Review.

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Glossary

Innate helper cell

A lymphoid cell that lacks antigen-specific receptors (such as B or T cell receptors) but that has the capacity to make cytokines associated with T helper (TH) cells (for example, the TH2-type cytokines interleukin-4 (IL-4), IL-5 and IL-13) in response to innate 'alarm' cytokines, such as IL-25 and IL-33.

Non-B, non-T cells

(NBNT cells). Cells that are distinct from immunoglobulin- or T cell receptor-bearing lymphocytes, basophils, eosinophils, mast cells and natural killer T cells and can produce T helper 2 (TH2)-type cytokines.

Tight junctions

A tight junction is a belt-like region of adhesion between adjacent epithelial or endothelial cells that regulates paracellular flux. Tight-junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludens proteins.

Recombination activating gene (RAG)-deficient mice

Recombination activating genes are involved in creating the double strand DNA breaks necessary for producing the rearranged gene segments that encode the complete protein chains of T cell and B cell receptors. Mice that are deficient for these genes fail to produce B and T cells owing to a developmental block in the gene rearrangement that is necessary for antigen receptor expression.

Anergy

A state of unresponsiveness that is sometimes observed in T and B cells that are chronically stimulated or are stimulated through the antigen receptor in the absence of co-stimulatory signals.

Regulatory B cells

Populations of B cells that downregulate immune responses. These cells are most often associated with production of the immunosuppressive cytokine interleukin-10.

T regulatory type 1 cells

(TR1 cells). A subset of CD4+ regulatory T cells that secrete high levels of interleukin-10 (IL-10) and downregulate T helper 1 (TH1) and TH2 cell responses in vitro and in vivo by a contact-independent mechanism mediated by the secretion of soluble IL-10 and transforming growth factor-β.

Hygiene hypothesis

This hypothesis originally proposed that the increased incidence of atopic diseases in westernized countries was a consequence of living in an overly clean environment, with reduced bacterial exposure predisposing to increased T helper 2 (TH2)-type allergic responses to harmless antigens. More recently, it has been proposed that an absence of exposure to a broader range of pathogens, including helminths, may weaken the immunoregulatory controls that exist to restrain allergy and autoimmune disease.

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Allen, J., Maizels, R. Diversity and dialogue in immunity to helminths. Nat Rev Immunol 11, 375–388 (2011). https://doi.org/10.1038/nri2992

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