Trends in Immunology
ReviewT cells in helminth infection: the regulators and the regulated
Section snippets
Helminths and the immune system
Helminth parasites establish and assimilate themselves for long periods in the host and immunoregulation plays a key role in their survival strategy [1]. Helminths are large, multicellular pathogens and the immune system has evolved a suite of specialized effector mechanisms centered around the Th2 pathway (Box 1) to degrade and eliminate them [2]. However, parasites have countered by engaging directly with host signals that regulate and tune effector pathways 3, 4. When the host response does
The regulators: regulatory T cells in helminth infection
Multiple types of immunosuppressive cells operate in the immune system, including CD4+Foxp3+ regulatory T cells (mostly expressing CD25), B cells and macrophages [6]. In addition, suppressive cytokines such as TGF-β and IL-10, produced by diverse hematopoietic and non-hematopoietic cells are integral to immunoregulatory pathways 7, 8. Although the complexity of regulatory cell types continues to be charted, CD4+CD25+Foxp3+ Tregs remain the most prominent population of immunoregulatory cells
Helminth infections drive Foxp3+ Treg responses
In murine infection models, helminth infections elicit both ‘natural’ and ‘adaptive’ Foxp3+ Treg cell responses, which dampen Th2 immunity. Foxp3+ Treg numbers can expand rapidly following filarial and gastrointestinal nematode infections, with significant increases within 3–7 days 15, 16, 17, 18, 19, 20. Moreover, CD4+Foxp3+ cells respond to infection more rapidly than CD4+Foxp3− effector T (Teff) cells, increasing their frequency and biasing the initial response towards a regulatory phenotype
Foxp3+ Tregs in resistance to helminth infections
Although the main role of Foxp3+ Tregs is to maintain tolerance and control excessive inflammatory responses, the trade-off is inhibited protective immune responses, a property exploited by helminth parasites to immunosuppress their host. Experimentally, two imperfect approaches are available to test whether Foxp3+ Tregs are required for parasite survival. Anti-CD25 antibodies can be used for long-term depletion of CD25+Foxp3+ Tregs, with the caveat that this also depletes activated Teffs while
Foxp3+ Tregs in the control of immune pathology
Immune regulation is a beneficial and essential aspect of host immunity in dampening potentially pathogenic inflammatory responses and Foxp3+ Tregs clearly control Th2-mediated immune pathology in helminth infections. For example, expanded and activated Foxp3+ Treg populations down-regulate Th2 responses towards the S. mansoni eggs that engender pathogenic reactions when trapped in tissue vasculature 25, 38 and the severity of egg-induced liver pathology is negatively correlated with Foxp3+
Natural versus adaptive Foxp3+ Treg cells
The natural and adaptive Foxp3+ Treg cells activated during helminth infections may have distinct or overlapping functions. The rapid expansion of total Foxp3+ cell numbers following infection suggests the stimulation of natural Tregs, and the effects of Treg depletion immediately prior to infection demonstrate the functional importance of this cell type. A key question is whether natural pre-committed Foxp3+ Tregs form the first line of regulation, while adaptive Foxp3+ Treg cells appear later
The regulated: Th2 effector responses in helminth infection
The long-term persistence of helminths presents the host with the challenge of maintaining CD4+ T cell responses for decades. Although Type 2 immunity is, in general, down-regulated in established helminth infections, the fate of the underlying Th2 effector cells in an environment of persistent infection and dominant immune-regulation is not known (Figure 2).
One possibility is that Th2 effector cells remain fully functional but are held in check by different extrinsic regulatory cells and their
Not all Type 2 responses are equal
Chronic helminth infections are associated with a shift in the overall Type 2 phenotype of the host. In filariasis and schistosomiasis, IL-5 is often down-regulated more than IL-4 55, 56, indicating modulation of selective constituents of Type 2 immunity rather than a global inhibition. In general, the chronic Type 2 profile can be seen as retaining the ‘inducer’ cytokine IL-4 while diminishing ‘effector’ cytokines, such as IL-5. A major conceptual advance was the description of a ‘modified’ or
Intrinsic regulation: anergy versus exhaustion?
A global change in the Type 2 phenotype towards a modified form may also reflect the differentiation of Th2 cells into an intrinsically unresponsive or hyporesponsive state. Initial evidence for T cell anergy was provided in human filariasis, where in vitro immune responsiveness could be restored by the addition of IL-2 [64]. The characterization of an anergic molecular signature within the PBL of filariasis patients, comprising c-cbl, cbl-b, Nedd4 and Itch, provides further evidence for the
Implications for therapeutic and protective memory responses
The development of an anergic (or possibly, exhausted) CD4+ Th2 cell phenotype has important implications for the treatment of infections and the development of memory. Even if extrinsic immune-regulation is ablated, Th2 effector cells will remain functionally impaired and unable to kill the parasite (Figure 2). In agreement with this, depletion of CD25+ Tregs during established L. sigmodontis infection is successful only if combined with blocking CTLA-4 or providing co-stimulation through GITR
Historical constraints and Th2 flexibility
In the setting of long-term regulated T cell responses, how much flexibility is there for the Type 2 response to overcome the constraint of a historically unresponsive status (Figure 3)? Does natural resistance take decades to develop because the host has to first rewrite or replace their initial regulated response, and how can this process be accelerated therapeutically? Interestingly, beekeepers that develop tolerance to bee stings via a modified Th2 response lose their unresponsive phenotype
Concluding remarks
By analyzing helminth infections, it is clear that regulatory and effector T cells form a long-term interrelationship that compromises immunity and promotes parasite survival. Recent findings on the generation, interactions and fates of both the regulators and the regulated during infection, provide a framework for applying the fundamental principles of T cell regulation to these highly prevalent diseases. Many key questions now require testing in experimental models to refine this framework,
Acknowledgments
We thank the Medical Research Council and the Wellcome Trust for support.
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