Neither interleukin‐4 receptor α expression on CD4⁺ T cells, or macrophages and neutrophils is required for protective immunity to Trichinella spiralis

Abstract

Summary The T helper type 2 (Th2) mediated expulsion of the gastrointestinal nematode Trichinella spiralis requires interleukin‐4 receptor α (IL‐4Rα) expression on both bone‐marrow‐derived and non‐bone‐marrow‐derived cells. To more definitively investigate the role of IL‐4/IL‐13 responsiveness in the development of protective immunity to T. spiralis, cell‐specific IL‐4Rα signalling on CD4+ T cells (Lckcre IL‐4Rα−/flox) and macrophages/neutrophils (LysMcre IL‐4Rα−/flox) was analysed on the BALB/c background. Infection of wild‐type and control IL‐4Rα−/flox mice induced a Th2‐type immune response with elevated IL‐4 cytokine production, parasite‐specific immunoglobulin G1 (IgG1), total IgE, intestinal mastocytosis and enteropathy. In contrast, global IL‐4Rα‐deficient BALB/c mice showed reduced worm expulsion, antibody production, intestinal mastocytosis and gut pathology. BALB/c mice generated with cell‐specific deletion of IL‐4Rα on CD4+ T lymphocytes or macrophages/neutrophils, controlled gastrointestinal helminth infection by eliciting a protective immune response comparable to that observed with wild‐type and IL‐4Rα−/flox controls. Together, this shows that the development of host protective Th2 responses accompanied by parasite loss is independent of IL‐4Rα expression on CD4+ T cells and macrophages/neutrophils.

Immunity to gastrointestinal nematode infections

“…66 Furthermore, with the exception of IL-4 in the skin, 67 IL-4 appears to be dispensable for N. brasiliensis expulsion. 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.…”

Macrophage proliferation, provenance, and plasticity in macroparasite infection

“…For example, Arginase and RELMα, products strongly associated with alternative macrophage activation, can act as negative feedback regulators directly limiting the Th2 response . Thus, it may not be surprising that efficient elimination of the gastrointestinal nematodes N. brasiliensis or Trichinella spiralis was unimpaired in LysMCre IL‐4Rα flox/− mice relative to WT . Critically, a role (or lack thereof) for AAMΦ in one infection system may not apply to all nematode infections as the Th2 effector mechanisms involved can be quite distinct .…”

Myeloid cell-specific expression of Ship1 regulates IL-12 production and immunity to helminth infection

“…Interestingly, mice with a macrophage-specific deletion of IL-4R develop normal protective T H 2 cell-dependent immune responses following infection with the parasitic helminths Nippostrongylus brasiliensis 21 or Trichinella spiralis . 22 In addition, mice treated with Arg1 inhibitors or mice deficient in Arg1 are not impaired in their ability to clear many helminth parasite infections. 23,24 Furthermore, depletion of macrophages in resistant C57BL / 6 mice during infection with the intestinal helminth parasite Trichuris muris 25 has no effect on the development of protective responses and parasite expulsion.…”