T cells in helminth infection: the regulators and the regulated

doi:10.1016/j.it.2012.01.001

Trends in Immunology

Volume 33, Issue 4, April 2012, Pages 181-189

https://doi.org/10.1016/j.it.2012.01.001 Get rights and content

Helminth parasites survive through a combination of parasite longevity, repeated re-infection and selective immune suppression to prevent protective Th2 responses. To counteract helminth-induced immunosuppression, and to induce long-term immunological memory, understanding of the multiple regulatory pathways within the T cell compartment is needed. Extrinsic inhibition by regulatory T cells is a key element of Th2 suppression. In addition, Th2 cells in chronic regulatory environments become functionally impaired, indicating cell-intrinsic regulation, which compromises protective Th2 memory. We discuss these pathways and consider the potential for reversing unresponsiveness through stimulatory signals or replacement by new responder populations. Future vaccine or therapeutic strategies should aim to minimize extrinsic regulatory effects and simultaneously negate Th2 anergy to drive effector responses into a long-term functionally competent state.

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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Trends in Immunology

ReviewT cells in helminth infection: the regulators and the regulated

Section snippets

Helminths and the immune system

The regulators: regulatory T cells in helminth infection

Helminth infections drive Foxp3+ Treg responses

Foxp3+ Tregs in resistance to helminth infections

Foxp3+ Tregs in the control of immune pathology

Natural versus adaptive Foxp3+ Treg cells

The regulated: Th2 effector responses in helminth infection

Not all Type 2 responses are equal

Intrinsic regulation: anergy versus exhaustion?

Implications for therapeutic and protective memory responses

Historical constraints and Th2 flexibility

Concluding remarks

Acknowledgments

Immunity

Microbes Infect.

Lancet

Lancet

Immunity

Curr. Opin. Immunol.

Blood

Helminth parasites: masters of regulation

Immunol. Rev.

Protective immune mechanisms in helminth infection

Nat. Rev. Immunol.

Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway

J. Exp. Med.

The S. mansoni glycoprotein ω-1 induces Foxp3 expression in NOD mouse CD4+ T cells

Eur. J. Immunol.

Immunopathology of schistosomiasis

Immunol. Cell Biol.

Diversity and dialogue in immunity to helminths

Nat. Rev. Immunol.

Transforming growth factor-β regulation of immune responses

Annu. Rev. Immunol.

IL-10: the master regulator of immunity to infection

J. Immunol.

Regulation of the immune response by helminth parasites: cellular and molecular mechanisms

Nat. Rev. Immunol.

Tr1 and naturally occurring regulatory T cells induce IgG4 in B cells through GITR/GITR-L interaction, IL-10 and TGF-β

Eur. J. Immunol.

Antigen-specific cellular hyporesponsiveness in a chronic human helminth infection is mediated by Th3/Tr1-type cytokines IL-10 and transforming growth factor-β but not by a Th1 to Th2 shift

Int. Immunol.

Regulatory networks induced by live parasites impair both Th1 and Th2 pathways in patent lymphatic filariasis: implications for parasite persistence

J. Immunol.

At homeostasis filarial infections have expanded adaptive T regulatory but not classical Th2 cells

J. Immunol.

Regulatory and activated T cells in human Schistosoma haematobium infections

PLoS ONE

Expansion and activation of CD4+CD25+ regulatory T cells in Heligmosomoides polygyrus infection

Eur. J. Immunol.

Expansion of Foxp3+ regulatory T cells in mice infected with the filarial parasite, Brugia malayi

J. Immunol.

Early recruitment of natural CD4+Foxp3+ regulatory T cells by infective larvae determines the outcome of filarial infection

Eur. J. Immunol.

Functional analysis of effector and regulatory T cells in a parasitic nematode infection

Infect. Immun.

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3+ cells

Eur. J. Immunol.

Strongyloides ratti infection induces expansion of Foxp3+ regulatory T cells that interfere with immune response and parasite clearance in BALB/c mice

J. Immunol.

Th2 responses to helminth parasites can be therapeutically enhanced by, but are not dependent upon, GITR-GITR ligand costimulation In vivo

J. Immunol.

T regulatory cell levels decrease in people infected with Schistosoma mansoni on effective treatment

Am. J. Trop. Med. Hyg.

Regulatory T cell in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparum

Eur. J. Immunol.

Naturally-occurring CD4+Foxp3+ regulatory T cells are an essential, IL-10-independent part of the immunoregulatory network in Schistosoma mansoni egg-induced inflammation

J. Immunol.

CTLA-4+ and CD4+CD25+ regulatory T cells inhibit protective immunity to filarial parasites in vivo

J. Immunol.

Pronounced phenotype in activated regulatory T cells during a chronic helminth infection

J. Immunol.

Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease

J. Exp. Med.

Efficient Treg depletion induces T-cell infiltration and rejection of large tumors

Eur. J. Immunol.

Regulatory T cells modulate Th2 responses induced by Brugia pahangi third-stage larvae

Review
T cells in helminth infection: the regulators and the regulated

Helminth infections drive Foxp3⁺ Treg responses

Foxp3⁺ Tregs in resistance to helminth infections

Foxp3⁺ Tregs in the control of immune pathology

Natural versus adaptive Foxp3⁺ Treg cells

The S. mansoni glycoprotein ω-1 induces Foxp3 expression in NOD mouse CD4⁺ T cells

Antigen-specific cellular hyporesponsiveness in a chronic human helminth infection is mediated by T_h3/T_r1-type cytokines IL-10 and transforming growth factor-β but not by a T_h1 to T_h2 shift

Expansion and activation of CD4⁺CD25⁺ regulatory T cells in Heligmosomoides polygyrus infection

Expansion of Foxp3⁺ regulatory T cells in mice infected with the filarial parasite, Brugia malayi

Early recruitment of natural CD4⁺Foxp3⁺ regulatory T cells by infective larvae determines the outcome of filarial infection

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3⁺ cells

Strongyloides ratti infection induces expansion of Foxp3⁺ regulatory T cells that interfere with immune response and parasite clearance in BALB/c mice

Naturally-occurring CD4⁺Foxp3⁺ regulatory T cells are an essential, IL-10-independent part of the immunoregulatory network in Schistosoma mansoni egg-induced inflammation

CTLA-4⁺ and CD4⁺CD25⁺ regulatory T cells inhibit protective immunity to filarial parasites in vivo

Selective depletion of Foxp3⁺ regulatory T cells induces a scurfy-like disease

Role for CTLA-4 but not CD25⁺ T cells during Schistosoma mansoni infection of mice