Innate and adaptive type 2 immune cell responses in genetically controlled resistance to intestinal helminth infection

Abstract

The nematode Heligmosomoides polygyrus is an excellent model for intestinal helminth parasitism. Infection in mice persists for varying lengths of time in different inbred strains, with CBA and C57BL/6 mice being fully susceptible, BALB/c partially so and SJL able to expel worms within 2–3 weeks of infection. We find that resistance correlates not only with the adaptive Th2 response, including IL-10 but with activation of innate lymphoid cell and macrophage populations. In addition, the titer and specificity range of the serum antibody response is maximal in resistant mice. In susceptible strains, Th2 responses were found to be counterbalanced by IFN-γ-producing CD4+ and CD8+ cells, but these are not solely responsible for susceptibility as mice deficient in either CD8+ T cells or IFN-γ remain unable to expel the parasites. Foxp3+ Treg numbers were comparable in all strains, but in the most resistant SJL strain, this population does not upregulate CD103 in infection, and in the lamina propria the frequency of Foxp3+CD103+ T cells is significantly lower than in susceptible mice. The more resistant SJL and BALB/c mice develop macrophage-rich IL-4Rα-dependent Type 2 granulomas around intestinal sites of larval invasion, and expression of alternative activation markers Arginase-1, Ch3L3 (Ym1) and RELM-α within the intestine and the peritoneal lavage was also strongly correlated with helminth elimination in these strains. Clodronate depletion of phagocytic cells compromises resistance of BALB/c mice and slows expulsion in the SJL strain. Thus, Type 2 immunity involves IL-4Rα-dependent innate cells including but not limited to a phagocyte population, the latter likely involving the action of specific antibodies.

Cultivation of <em>Heligmosomoides Polygyrus:</em> An Immunomodulatory Nematode Parasite and its Secreted Products

“…Susceptibility to infection with H. polygyrus is controlled to a large degree by the genetic background of the mouse strain ( Table 1); C57BL/6 and CBA mice are highly susceptible 21,22 . For maintenance of the parasite life cycle, the F1 hybrid between these two strains has been chosen for its ability to withstand much higher worm burdens without morbidity (excessive intestinal epithelial damage) compared to either parental strain.…”

Immunity to gastrointestinal nematode infections

“…Similarly, whereas resident intestinal macrophages are mostly suppressive in nature and do not act inflammatory to pathogen stimulation, type 2 cytokines give rise to alternatively activated macrophages that might contribute to the expulsion of certain parasites. 75,192,203,204 Furthermore, macrophages in the intestinal mucosa are also likely to play an important role in tissue repair, as has been shown in various settings of inflammation. [205][206][207][208][209][210] Whereas most research on host-parasite interactions has focused on the underlying factors that govern resistance and susceptibility, the long-term consequences of both acute and chronic worm infections are largely unexplored.…”

“…61,68 The redundancy between IL-4 and IL-13 likely stems from their shared usage of the IL-4Ra subunit, [69][70][71] although interestingly, IL-4Ra deficiency in T cells has no impact on worm expulsion during either T. spiralis, 72 H. polygyrus, 73 or N. brasiliensis 61,62 infections, in contrast to total IL-4Ra ablation. 63,[73][74][75] Instead, IL-4 might need to be produced rather than recognized by T cells, as it is mostly secreted by follicular helper T cells to promote IgG1 class switching of B cells. 68 Nonetheless, IL-4 production by ILC2 has recently been implicated in the generation of protective T cell immunity to H. polygyrus, and interestingly was dependent on leukotriene D4.…”

A sticky end for gastrointestinal helminths; the role of the mucus barrier

“…More recently, neuropeptide neuromedin U signalling has been indicated to be a potent type 2 cytokine initiator; capable of causing activation and proliferation of ILC2s, and associated with accelerated expulsion of N. brasiliensis 53. ILC2s are primed early during H. polygyrus 54 and N. brasiliensis infection,55 providing a source of IL‐13 which promotes the production of type 2 cytokines and goblet cell hyperplasia. More recently, data has emerged to suggest tuft cells are critical in orchestrating signalling cues for type 2‐mediated immunity during GI nematode infections, facilitating the communication between the epithelium and the underlying immune cells 56.…”

“…More recently, data has emerged to suggest tuft cells are critical in orchestrating signalling cues for type 2‐mediated immunity during GI nematode infections, facilitating the communication between the epithelium and the underlying immune cells 56. Tuft cells are a chemosensory cell of the gut,57 and the induction of tuft cells has been demonstrated to provide an early supply of IL‐25 during N. brasiliensis , T. spiralis and H. polygyrus infection, which in turn leads to the induction of IL‐13 producing ILC2s and results in a feedforward system to cause tuft cell hyperplasia54, 55 (Figure 4). Furthermore, goblet cell hyperplasia during N. brasiliensis infection is dependent on the presence of tuft cells, as mice deficient in tuft cells (Pou2f3 −/− mice) not only have reduced IL‐25 expression and ILC2 expansion, but goblet cell hyperplasia did not occur and animals were unable to expel the parasite, unlike their wild‐type counterparts 58.…”