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Regulatory T‐cells in helminth infection: induction, function and therapeutic potential

White, Madeleine P. J., McManus, Caitlin M., Maizels, Rick M.·2020·Immunology
DOI 10.1111/imm.13190PMC PMC7341546
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Abstract

Summary: Helminth parasites infect an alarmingly large proportion of the world's population, primarily within tropical regions, and their ability to down‐modulate host immunity is key to their persistence. Helminths have developed multiple mechanisms that induce a state of hyporesponsiveness or immune suppression within the host; of particular interest are mechanisms that drive the induction of regulatory T‐cells (Tregs). Helminths actively induce Tregs either directly by secreting factors, such as the TGF‐β mimic Hp‐ TGM, or indirectly by interacting with bystander cell types such as dendritic cells and macrophages that then induce Tregs. Expansion of Tregs not only enhances parasite survival but, in cases such as filarial infection, Tregs also play a role in preventing parasite‐associated pathologies. Furthermore, Tregs generated during helminth infection have been associated with suppression of bystander immunopathologies in a range of inflammatory conditions such as allergy and autoimmune disease. In this review, we discuss evidence from natural and experimental infections that point to the pathways and molecules involved in helminth Treg induction, and postulate how parasite‐derived molecules and/or Tregs might be applied as anti‐inflammatory therapies in the future.

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Figure 1 Overview of events in Treg expansion by helminths. (1) Early expansion of natural regulatory T‐cells (nTreg) by helminths within the first 3–7 days. (2) Helminth excretory−secretory (ES) products induce naïve CD4+ T‐cells to become Tregs. (3) ES products polarize dendritic cells (DCs) towards a tolerogenic phenotype capable of inducing Tregs. (4) M2 macrophage polarization following IL‐33 release by damaged epithelium, which then induce Tregs through an undefined mechanism. (5) Helminth proximity to Peyer's patch (PP) causes Treg expansion. It is as yet unclear whether Treg events (1)−(4) occur in either or both the lamina propria of the small intestine and the draining mesenteric lymph nodes, and hence no distinction is made in this figure.
Figure 1 Overview of events in Treg expansion by helminths. (1) Early expansion of natural regulatory T‐cells (nTreg) by helminths within the first 3–7 days. (2) Helminth excretory−secretory (ES) products induce naïve CD4+ T‐cells to become Tregs. (3) ES products polarize dendritic cells (DCs) towards a tolerogenic phenotype capable of inducing Tregs. (4) M2 macrophage polarization following IL‐33 release by damaged epithelium, which then induce Tregs through an undefined mechanism. (5) Helminth proximity to Peyer's patch (PP) causes Treg expansion. It is as yet unclear whether Treg events (1)−(4) occur in either or both the lamina propria of the small intestine and the draining mesenteric lymph nodes, and hence no distinction is made in this figure.CC BY · PubMed Central
Figure 2 Tregs in response to helminth infection in different tissues. Liver, upregulation of GITR, CD103 and CTLA‐4 on Tregs in response to Schistosoma mansoni infection and exposure to eggs trapped in the liver; peritoneal cavity, CD103 and CTLA‐4 on Tregs are upregulated when infected with the filarial nematode Brugia malayi; large intestine, increase in CD103 expression on Tregs in mice carrying duodenal infection with Heligmosomoides polygyrus, Treg expression of RORγt and ST2 are as yet unknown during helminth infection; pleural cavity, Litomosoides sigmodontis infection upregulates ICOS, GITR, PD‐1 and CTLA‐4 expression on Tregs; spleen, S. mansoni infection increases the expression of GITR and CTLA‐4 on Tregs; small intestine, Trichinella spiralis infection induces high levels of CTLA‐4 expression on Tregs and H. polygyrus infection upregulates CD103 and CTLA‐4 as measured on Tregs in the mesenteric lymph nodes, a surrogate of the populations in the small intestine lamina propria. CTLA‐4, cytotoxic T‐lymphocyte‐associated protein 4; GITR, glucocorticoid‐induced tumour necrosis factor receptor; ICOS, inducible T‐cell co‐stimulator; PD‐1, programmed cell death protein 1; RORγt RAR‐related orphan receptor gamma.
Figure 2 Tregs in response to helminth infection in different tissues. Liver, upregulation of GITR, CD103 and CTLA‐4 on Tregs in response to Schistosoma mansoni infection and exposure to eggs trapped in the liver; peritoneal cavity, CD103 and CTLA‐4 on Tregs are upregulated when infected with the filarial nematode Brugia malayi; large intestine, increase in CD103 expression on Tregs in mice carrying duodenal infection with Heligmosomoides polygyrus, Treg expression of RORγt and ST2 are as yet unknown during helminth infection; pleural cavity, Litomosoides sigmodontis infection upregulates ICOS, GITR, PD‐1 and CTLA‐4 expression on Tregs; spleen, S. mansoni infection increases the expression of GITR and CTLA‐4 on Tregs; small intestine, Trichinella spiralis infection induces high levels of CTLA‐4 expression on Tregs and H. polygyrus infection upregulates CD103 and CTLA‐4 as measured on Tregs in the mesenteric lymph nodes, a surrogate of the populations in the small intestine lamina propria. CTLA‐4, cytotoxic T‐lymphocyte‐associated protein 4; GITR, glucocorticoid‐induced tumour necrosis factor receptor; ICOS, inducible T‐cell co‐stimulator; PD‐1, programmed cell death protein 1; RORγt RAR‐related orphan receptor gamma.CC BY · PubMed Central

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Metadata

Authors
White, M. P. J., McManus, C. M., & Maizels, R. M.
Venue
Immunology
Publisher
Wiley
Published
2020-04-19
Volume
160
Issue
3
Pages
248-260
ISSN
  • 0019-2805
  • 1365-2567
DOI
10.1111/imm.13190
PMC
PMC7341546
Cited by
114
References
8
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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