Abstract
IL-25, an IL-17 family cytokine, derived from epithelial cells was shown to regulate Th2- and Th9-type immune responses. We previously reported that IL-25 was important in promoting efficient protective immunity against T. spiralis infection; however, the cellular targets of IL-25 to elicit type-2 immunity during infection have not yet been addressed. Here, we investigated IL-25-responding cells and their involvement in mediating type-2 immune response during T. spiralis infection. ILC2 and CD4+ Th2 cells residing in the gastrointestinal tract of T. spiralis infected mice were found to express high levels of surface interleukin-17 receptor B (IL-17RB), a component of the IL-25 receptor. Following T. spiralis infection, activated ILC2s upregulated surface MHCII expression and enhanced capacity of effector T helper cell in producing antigen-specific Th2 and Th9 cytokines through MHCII-dependent interactions. Reciprocally, lack of CD4+ T helper cells impaired ILC2 function to produce type 2-associated cytokines in responding to IL-25 during T. spiralis infection. Furthermore, mice deficient in IL-17RB showed markedly reduced ILC2 numbers and antigen-specific Th2 and Th9 cytokine production during T. spiralis infection. The Il17rb-/- mice failed to mount effective antigen specific Th2 and Th9 functions resulting in diminished goblet cell and mast cell responses, leading to delayed worm expulsion in the intestines and muscles. Thus, our data indicated that ILC2s and CD4+ Th2 cells are the predominant cellular targets of IL-25 following T. spiralis infection and their collaborative interactions may play a key role in mounting effective antigen-specific Th2 and Th9 cytokine responses against T. spiralis infection.
Highlights
Different tissue-dwelling parasitic nematodes that possess distinct intestinal niches and life cycles may confer different susceptibility to specific immune cell effector functions
To identify the immune cells responsible for interleukin 25 (IL-25)-mediated protective immunity against T. spiralis infection, we examined lamina propria cells from the intestines of mice infected with T. spiralis using multicolor flow cytometric analysis
To better understand the involvement of these cells in IL25-mediated type-2 immunity against T. spiralis infection, we examined the interleukin-17 receptor B (IL-17RB)-expressing cells in the small intestines and mesenteric lymph nodes of mice infected with T. spiralis at different time periods in 4-GFP reporter (4GET) mice using the previously described strategy
Summary
Different tissue-dwelling parasitic nematodes that possess distinct intestinal niches and life cycles may confer different susceptibility to specific immune cell effector functions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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