Review T cells in helminth infection: the regulators and the regulated Matthew D. Taylor, Nienke van der Werf and Rick M. Maizels Institute of Immunology and Infection Research, University of Edinburgh, Ashworth Laboratories, West Mains Road, Edinburgh EH9 3JT, UK Helminth parasites survive through a combination of par- (mostly expressing CD25), B cells and macrophages [6]. asite longevity, repeated re-infection and selective im- In addition, suppressive cytokines such as TGF-b and IL- mune suppression to prevent protective Th2 responses. 10, produced by diverse hematopoietic and non-hemato- To counteract helminth-induced immunosuppression, poietic cells are integral to immunoregulatory pathways and to induce long-term immunological memory, under- [7,8]. Although the complexity of regulatory cell types + + + standing of the multiple regulatory pathways within the T continues to be charted, CD4 CD25 Foxp3 Tregs remain cell compartment is needed. Extrinsic inhibition by regu- the most prominent population of immunoregulatory latory T cells is a key element of Th2 suppression. cells operating during helminth infections described to In addition, Th2 cells in chronic regulatory environments date. become functionally impaired, indicating cell-intrinsic Immunoregulation in helminth infection was first rec- regulation, which compromises protective Th2 memory. ognized in early human studies, because peripheral T cells We discuss these pathways and consider the potential in infected patients were frequently unresponsive to para- for reversing unresponsiveness through stimulatory site antigens and responses to bystander antigens (includ- signals or replacement by new responder populations. ing allergens and vaccines) were also reduced [9]. In Future vaccine or therapeutic strategies should aim to addition, antibody isotypes were distorted, with exception- minimize extrinsic regulatory effects and simultaneously ally high concentrations of IgG4 that is, in part, attribut- negate Th2 anergy to drive effector responses into a long- able to Treg activity [10]. TGF-b and IL-10-producing term functionally competent state. Tregs were then cloned from Onchocerca volvulus-infected patients [11], and higher Foxp3 expression was found in Helminths and the immune system peripheral blood T cells from cases of active lymphatic Helminth parasites establish and assimilate themselves filariasis and schistosomiasis [12–14]. This field research for long periods in the host and immunoregulation plays a provides a firm basis for investigating the role of Tregs in key role in their survival strategy [1]. Helminths are large, experimental infection models. multicellular pathogens and the immune system has evolved a suite of specialized effector mechanisms cen- + Helminth infections drive Foxp3 Treg responses tered around the Th2 pathway (Box 1) to degrade and In murine infection models, helminth infections elicit both eliminate them [2]. However, parasites have countered by + ‘natural’ and ‘adaptive’ Foxp3 Treg cell responses, which engaging directly with host signals that regulate and tune + dampen Th2 immunity. Foxp3 Treg numbers can expand effector pathways [3,4]. When the host response does rapidly following filarial and gastrointestinal nematode overcome parasite resistance, it is often at the cost of infections, with significant increases within 3–7 days incurring pathology [5]; perhaps for this reason immunity + + [15–20]. Moreover, CD4 Foxp3 cells respond to infection is restrained by parasite immunomodulators and by en- + more rapidly than CD4 Foxp3À effector T (Teff) cells, in- dogenous regulatory mechanisms. We review recent data creasing their frequency and biasing the initial response showing how regulatory networks develop through a com- + + towards a regulatory phenotype [16,17,21]. Early Foxp3 bination of extrinsic inhibition by Foxp3 regulatory T Treg responses are not merely homeostatic as induction cells (Tregs) and intrinsic regulation of Th2 effector cell requires live (rather than heat-killed) parasites [16], where- populations, through processes such as anergy, exhaus- as other infections, such as Toxoplasma gondii, cause a tion or adaptive tolerance. The impact of these regulatory + precipitous loss of Foxp3 Tregs [22]. Conversely, drug- networks on the development of Th2 memory, and the + induced clearance of helminths reduces Foxp3 Treg num- potential for reversing unresponsiveness through stimu- bers and improves responses to bystander antigens [23,24]. latory signals and/or replenishing effector populations, In parallel with quantitative expansion of Tregs, hel- are discussed. minths can also induce elevated expression of CD103 and + other activation markers on Foxp3 Tregs [15–17,25–27], The regulators: regulatory T cells in helminth infection which exert a more potent suppressive function [15,18]. Multiple types of immunosuppressive cells operate in the Thus, the regulatory capacity of the Treg subset in vivo + + + immune system, including CD4 Foxp3 regulatory T cells may be reflected not simply by the proportion of Foxp3 cells, but more accurately by expression of activation Corresponding authors: Taylor, M.D. ([email protected]); Maizels, R.M. ([email protected]). markers. 1471-4906/$ – see front matter ß 2012 Published by Elsevier Ltd. doi:10.1016/j.it.2012.01.001 Trends in Immunology, April 2012, Vol. 33, No. 4 181 Review Trends in Immunology April 2012, Vol. 33, No. 4 Box 1. Mechanisms of Th2 immunity to helminths Two main arenas are considered: in the gastrointestinal tract, of the tissues, skin-penetrating helminth larvae can be intercepted by mucosal immunity involves both innate and adaptive populations. IL-5-dependent eosinophils; bloodstream microfilariae are cleared by Innate effector mechanisms include goblet cells, which increase IgM-dependent antibody mechanisms; and in internal organs multi- mucin production, switch mucin types (e.g. to MUC5AC) and release ple (and potentially redundant) populations or granulocytes and the effector protein resistin-like molecule-b (RELM-a); mast cells and macrophages are guided by chemokines, cytokines and antibodies to alternatively activated macrophages, each driven by type 2 cytokines attack helminths through pre-formed mediators and reactive meta- from Th2 and innate lymphoid (‘nuocyte’) cells. In the different setting bolites. Mucosal Tissue Epidermis (IgE) Skin IL-33, TSLP IL-5 IL-13 IL-25, IL-33 Eosinophils Nuocyte FcR Mast Cells Th2 IgM MCP proteases IL-4R cell Bloodstream open tight junctions IL-13 allowing fluid egress IgG neutralization IL-4 (e.g. blocking Tissue immunomodulation) Epithelial cell turnover (e.g. lung) goblet cell hyperplasia Macrophage-rich “type 2” IgG opsonization granuloma in intestinal wall B cell Arginase, RELM-α, YM- 1 Granule contents Mucins (MUC5AC) RELMβ IgA, IgG1 inhibit motility and CXCR2 FcεR FcεR reduce feeding fitness Neutrophils Eosinophils Basophils Macrophages IL-5 IL-3 IL-4 Reduced viability, lower Th2 IL-13 transmission, early expulsion cell + Foxp3 Tregs in resistance to helminth infections Likewise, depletion of Tregs in Foxp3-DTR Strongyloides + Although the main role of Foxp3 Tregs is to maintain ratti-infected mice increases host resistance if performed tolerance and control excessive inflammatory responses, within the first 4 days [20]. In infections with both filarial the trade-off is inhibited protective immune responses, Litomosoides sigmodontis and geohelminth S. ratti para- a property exploited by helminth parasites to immuno- sites, increased resistance appears to act on the adult, suppress their host. Experimentally, two imperfect rather than larval, stage [17,20] and long-term Th2 en- + approaches are available to test whether Foxp3 Tregs hancement outlasts the direct effects of depletion [17]. In + are required for parasite survival. Anti-CD25 antibodies these settings, Foxp3 Tregs inhibit the priming of Th2 + + can be used for long-term depletion of CD25 Foxp3 responses and limit the quantity or functional quality of Tregs, with the caveat that this also depletes activated the effector T cell pool available at later times. + Teffs while sparing CD25ÀFoxp3 Tregs. Alternatively, a Reflecting the diversity of helminth life histories, it is diphtheria toxin receptor (DTR) transgene expressed not surprising that each species displays a unique interac- + specifically by Foxp3 cells [28,29] permits short-term tion with Tregs. For example, in Trichuris muris infection, + depletion of Foxp3 Tregs, but this approach is less early intervention with anti-GITR, but not anti-CD25, applicable to chronic infection models. antibodies is most effective at reducing worm loads [31]. + The rapid rise in Foxp3 Treg numbers in infection Anti-CD25 depletion is reported to be ineffective at boost- suggests that a suppressive response pre-empts establish- ing immunity to other helminths, including Schistosoma ment of Th2 immunity. Accordingly, antibody-mediated mansoni [32,33] and Trichinella spiralis [34]. Experiments + depletion of CD25 Treg cells prior to infection increases with Foxp3-DTR mice will be interesting in this regard Th2 responses to, and killing of, filarial parasites [17,30]. and, although Foxp3-depleted mice are not more resistant 182 Review Trends in Immunology April 2012, Vol. 33, No. 4 + to the gastrointestinal nematode Heligmosomoides poly- of helminth immunity in humans [43–45] and with Foxp3 + gyrus in the first 14 days of infection [19], a longer time may Tregs in other settings, helminth-induced Foxp3 Tregs be required