Interleukin‐4‐ and interleukin‐13‐mediated host protection against intestinal nematode parasites

Abstract

Intestinal worm infections characteristically induce T-helper 2 cell (Th2) cytokine production. We reviewed studies performed with mice infected with either of two intestinal nematode parasites, Nippostrongylus brasiliensis or Trichinella spiralis, that evaluate the importance of the Th2 cytokine interleukin-4 (IL-4) and IL-13 in protection against these parasites. These studies demonstrate that while IL-4/IL-13 protect against both parasites by activating signal transducer and activator of transcription 6 (Stat6) through IL-4 receptor alpha (IL-4Ralpha) ligation, Stat6 activation protects against these parasites through different mechanisms. Stat6-dependent gene transcription promotes expulsion of N. brasiliensis solely through effects on non-bone marrow-derived cells that may include enhancement of intestinal smooth muscle contractility, changes in intestinal epithelial cell function, and increased intestinal mucus secretion. In contrast, Stat6 signaling promotes immunity to T. spiralis both through effects on bone marrow-derived cells that can be reproduced by treating mice with IL-4 or IL-13 and through effects on non-bone marrow-derived cells. The former effects appear to include T-cell-dependent induction of intestinal mastocytosis, while the latter sensitize non-bone marrow-derived cells to mast cell-produced mediators. We argue that a limited ability of the host immune system to distinguish among different nematode parasites has led to the evolution of a stereotyped Th2 response that activates a set of effector mechanisms that protects against most intestinal nematode parasites.

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

“…Furthermore, the physiological changes provoked by the worm infection, such as epithelial cell proliferation and goblet cell hyperplasia, were similar in Tregdepleted and control mice. Thus, it seems that H. p. bakeri, which generally leads to chronic infections, tolerates a broad spectrum of Th2-mediated immune and physiological reactions compared with other intestinal nematodes such as Nippostrongylus brasiliensis, T. muris or T. spiralis, which are more efficiently expelled in acute infections [37,38].In conclusion, our data show that Treg are crucial for the control of helminth-induced pathological changes in the intestine and for limiting Th2 responses. Further studies will have to show whether Treg are involved in mediating the general immunosuppression seen in chronic intestinal nematode infections.…”

“…The general view suggests that expulsion of adult intestinal nematodes is critically dependent on CD4 1 T cells secreting the Th2 effector cytokines and that these cytokines lead to an inhospitable environment, possibly enabling the expulsion of the parasites in the chronic phase of infection [37,38]. It has also been shown that the application of high doses of recombinant IL-4 abrogates primary infections with H. p. bakeri [39].…”

“…Furthermore, the physiological changes provoked by the worm infection, such as epithelial cell proliferation and goblet cell hyperplasia, were similar in Tregdepleted and control mice. Thus, it seems that H. p. bakeri, which generally leads to chronic infections, tolerates a broad spectrum of Th2-mediated immune and physiological reactions compared with other intestinal nematodes such as Nippostrongylus brasiliensis, T. muris or T. spiralis, which are more efficiently expelled in acute infections [37,38].…”

“…However, the release of a broad spectrum of Th2 cytokines was impaired after anti-CD25 Ab treatment, arguing for the side-by-side depletion of Th2 effector cells [23]. In contrast, our model showed that the selective Treg depletion strongly promoted the Th2 response to H. p. bakeri antigen.The general view suggests that expulsion of adult intestinal nematodes is critically dependent on CD4 1 T cells secreting the Th2 effector cytokines and that these cytokines lead to an inhospitable environment, possibly enabling the expulsion of the parasites in the chronic phase of infection [37,38]. It has also been shown that the application of high doses of recombinant IL-4 abrogates primary infections with H. p. bakeri [39].…”

Alternatively activated macrophages in helminth infections

“…Elements of the Th2-type response can control pathologic Th1-type inflammation and also marshal effective helminth resistance; for example, the Th2-type response has a demonstrated role in the expulsion of several intestinal nematode parasites [43,44]. Clearly AAMΦs may contribute to resistance by controlling Th1-type immunity and thereby promoting a potent and polarized Th2-type response.…”