Abstract
Interleukin 25 (IL-25) is a major 'alarmin' cytokine, capable of initiating and amplifying the type immune response to helminth parasites. However, its role in the later effector phase of clearing chronic infection remains unclear. The helminth Heligmosomoides polygyrus establishes long-term infections in susceptible C57BL/6 mice, but is slowly expelled in BALB/c mice from day 14 onwards. We noted that IL-25R (Il17rb)-deficient BALB/c mice were unable to expel parasites despite type 2 immune activation comparable to the wild-type. We then established that in C57BL/6 mice, IL-25 adminstered late in infection (days 14-17) drove immunity. Moreover, when IL-25 and IL-4 were delivered to Rag1-deficient mice, the combination resulted in near complete expulsion of the parasite, even following administration of an anti-CD90 antibody to deplete innate lymphoid cells (ILCs). Hence, effective anti-helminth immunity during chronic infection requires an innate effector cell population that is synergistically activated by the combination of IL-4Rα and IL-25R signaling.
Highlights
Type 2 immunity is generated by the immune system in response to a range of environmental challenges from helminth worm parasites, ectoparasites and allergens (Hammad and Lambrecht, 2015; Harris and Loke, 2017)
We first took the approach of analysing individual cell types within BALB/c and Il17rb–/– mice and found equivalent increases in total and IL13-expressing innate lymphoid cells (ILCs) in the mesenteric lymph node (MLN, Figure 1E,F) in both strains at day 14 postinfection, and similar increases in the number of Siglec-F-CD11b+Ly6C/G+ myeloid cells in the peritoneal lavage (PL) (Figure 1G)
Generation of the type 2 immune response, and protection from helminth parasite infection, requires sustained interaction and participation of both innate and adaptive immune cells (Allen and Maizels, 2011; Grencis, 2015; Harris and Loke, 2017; Van Dyken et al, 2016). Alarmins such as Interleukin 25 (IL-25) are potent activators of type 2 immunity, but as we report here, can play an even more important role in stimulating and mobilising effector mechanisms to expel infection
Summary
Type 2 immunity is generated by the immune system in response to a range of environmental challenges from helminth worm parasites, ectoparasites and allergens (Hammad and Lambrecht, 2015; Harris and Loke, 2017). We studied chronic infection with the nematode H. polygyrus, in which induction over the first 7–10 days can be analysed separately from the subsequent expulsion phase: in so doing, we report that IL-25 is redundant for Th2 initiation, but acts during the later phase of effector expulsion against this helminth parasite. Such a downstream role is consistent with recent reports demonstrating a role for IL-25 in protective immunity to a secondary infection with H. polygyrus, following drug clearance of a primary infection (Pei et al, 2016), or vaccination with parasite secreted antigens (Hewitson et al, 2015). A critical role for IL-25 in a late-stage immune response is evident in airway inflammation models, in which it plays a central role in stimulating inflammatory myeloid cells and promoting airway remodeling (Gregory et al, 2013; Petersen et al, 2012), or in driving allergic reactions to airway challenge in previously sensitized mice (Ballantyne et al, 2007; Cayrol and Girard, 2018)
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