IL‐1‐dependent, IL‐1R1‐independent resistance to gastrointestinal nematodes

Abstract

IL-1 null mice are unable to expel the intestinal nematode Trichuris muris; whereas WT littermates exhibit sterile immunity. Intriguingly the essential signalling components IL-1R1 and IL-1R accessory protein (AcP) are dispensable for expulsion of this parasite. IL-1 is thus critical for CD41 Th2-mediated immunity to T. muris; however, this action is independent of the established IL-1 signalling receptor. We also present data demonstrating that both IL-1a and IL-1b induce measurable effects on T. muris primed cells isolated from IL-1R1 or IL-1R AcP null mice. MLN cells from these mice restimulated with parasite antigen proliferated at a greater rate and produced more cytokines in response to exogenous IL-1. This ability to respond to IL-1 was restricted to these parasite-primed cells and importantly was not evident in cells from naïve gene null mice. These in vitro data are consistent with the observed ability of mice with compromised IL-1 signalling to expel the parasite, bolstering the premise that an alternative IL-1 signalling mechanism is accessible in the context of an intestinal helminth-driven Th2 immune response.Key words: Cytokine . Infection . Parasitic-helminth . Proinflammatory . T cells IntroductionIL-1 is a potent molecule; indeed when unregulated the resultant inflammatory cytokine cascade has profound pathological effects [1,2]. Thus by necessity IL-1 bioactivity is tightly controlled, requiring both posttranslational processing and a signalling receptor containing IL-1R1 and IL-1R accessory protein (AcP). This pathway to IL-1 action is policed by a decoy receptor IL-1R2, a natural sink for IL-1 [3] and IL-1RA, which competitively binds IL-1R1, preventing IL-1RAcP recruitment and signal transduction [4]. Importantly, IL-1RA only weakly interacts with IL-1R2, thus preventing the inhibition of the inhibitor [5]. This pleiotropic cytokine plays critical roles in a variety of inflammatory and non-inflammatory diseases. Pathological functions have been demonstrated in rheumatoid arthritis [6][7][8], Alzheimer's disease [9], multiple myeloma [10] and leukaemia [11][12][13]. Importantly for this study the involvement of IL-1 in the inflamed intestinal mucosa is also well established. Patients with ulcerative colitis significantly over express , with the principle sources identified as colon subepithelial macrophages [19,20], follicular epithelial M cells [21] and lamina propria T cells [22]. IL-1 also influences adaptive immunity, altering the CD4 1 Th-cell balance, though published data demonstrate contradictory changes in both Th1 and Th2 immune polarisation [23][24][25][26][27][28]. For example, IL-1a/b null mice show reduced Th2 responses to ovalbumin-induced airway hypersensitivity [29,30], whereas conversely, IL-1a has been shown to enhance Th1-driven immunity to Leishmania major in BALB/c mice [31]. Thus understanding the interplay of IL-1 and T-cell polarisation is complex and highly dependent on model, strain of mouse and method of IL-1 manipulation. Here, to better understand this role of IL...

T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy

“…These analyses predicted that IL-1R signaling would be compromised in Trim24 −/− T cells. In line with this prediction, IL-1R signaling is required for T H 2-dependent immunity (36,37) and T H 2-mediated airway allergy (38,39), supporting observations presented here with Trim24 −/− T cells. Specifically, IL-1 signaling is required to activate T H 2 cells in vivo (13,40), and, as we show here, IL-1R signaling in T cells can exacerbate T H 2-driven airway allergy.…”

“…Several lines of evidence support this Trim24/IL-1 pathway. First, it has been widely reported that IL-1 signaling is required for T H 2-mediated immunity and allergy (36)(37)(38)(39). More specifically, IL-1 signaling is required to activate T H 2 cells directly in vivo (13,40).…”

The S. mansoni glycoprotein ω‐1 induces Foxp3 expression in NOD mouse CD4+ T cells

“…Our finding showing increased production of IL-1b by LPS and o-1-stimulated BMDCs is consistent with this observation. IL-1b is a pleiotropic cytokine that has been shown to play a role in many different T-cell responses [35][36][37] but of particular interest is the observation the IL-1b plays a key role in helminth infections through its influence on Th2 responses and worm expulsion [38,39].…”

MyD88 Signaling Inhibits Protective Immunity to the Gastrointestinal Helminth Parasite Heligmosomoides polygyrus

“…These data also raise broader questions about the role of IL-1 signaling during helminth infections, as IL-1α and IL-1β appear to promote protective Th2 responses against the helminth parasite Trichuris muris (56), yet the IL-1R is reportedly not necessary for protective immunity (57). Moreover, a recent study reported that IL-1β–deficient mice are more resistant to H. polygyrus (34), again indicating that a ligand-dependent, but IL-1R–independent, pathway yet to be defined is important in immunity to helminths.…”