Parasitic helminths are a major cause of chronic human disease, affecting more than 3 billion people worldwide. Host protection against most parasitic helminths relies upon Type 2 cytokine production, but the mechanisms that regulate interleukin (IL) 4 and 13 production from CD4 + T helper 2 cells (T H 2) and innate lymphoid type 2 cells (ILC2s) remain incompletely understood. The epithelial cell-derived cytokines IL-25 and IL-33 promote Type 2 responses, but the extent of functional redundancy between these cytokines is unclear and whether Type 2 memory relies upon either IL-25 or IL-33 is unknown. Herein, we demonstrate a pivotal role for IL-33 in driving primary and anamnestic immunity against the rodent hookworm Nippostrongylus brasiliensis. IL-33-deficient mice have a selective defect in ILC2-derived IL-13 during both primary and secondary challenge infections but generate stronger canonical CD4 + T helper 2 cells responses (IL-4, IgE, mast cells, and basophils) than WT controls. Lack of IL-13 production in IL-33-deficient mice impairs resistin-like molecule beta (RELMβ) expression and eosinophil recruitment, which are two mechanisms that eliminate N. brasiliensis parasites from infected hosts. Thus, IL-33 is requisite for IL-13 but not IL-4-driven Type 2 responses during hookworm infection. mucosal immunity | gastrointestinal nematode | inflammation

Background Increased IL-17A production has been associated with more severe asthma, however the mechanisms whereby IL-17A may contribute to IL-13-driven pathology in asthma remain unclear. Objective We sought to gain mechanistic insight into how IL-17A can influence IL-13-driven responses. Methods The effect of IL-17A on IL-13-induced airway hyperresponsiveness (AHR), gene expression, mucus hypersecretion, and airway inflammation was assessed using in vivo models of IL-13-induced lung pathology and in vitro culture of murine fibroblast cell lines and primary fibroblasts, and human epithelial cell lines or primary human epithelial cells exposed to IL-13, IL-17A, or IL-13 and IL-17A. Results Compared to mice given intratracheal IL-13 alone, those exposed to IL-13 and IL-17A displayed augmented AHR, mucus production, airway inflammation and IL-13-induced gene expression. In vitro, IL-17A enhanced IL-13-induced gene expression in asthma-relevant murine and human cells. In contrast to the exacerbating influence of IL-17A on IL-13-induced responses, co-exposure to IL-13 inhibited IL-17A-driven antimicrobial gene expression in vivo and in vitro. Mechanistically, in both primary human and murine cells, IL-17A-driven elevation of IL-13-induced gene expression was associated with enhanced IL-13-driven STAT6 activation. Conclusions Our data suggest that IL-17A contributes to asthma pathophysiology by increasing the capacity of IL-13 to activate intracellular signaling pathways such as STAT6. These data represent the first mechanistic explanation of how IL-17A may directly contribute to the pathogenesis of IL-13-driven pathology.

Studies examining the role of PD-1 family members in allergic asthma have yielded conflicting results. Using a mouse model of allergic asthma, we find that blockade of PD-1/PD-L1 has distinct influences on different CD4+ T cell subsets. PD-1/PD-L1 blockade enhances AHR not by altering the magnitude of the underlying Th2 immune response, but by allowing the development of a concomitant Th17 immune response. Supporting differential CD4+ T cell responsiveness to PD-1-mediated inhibition, naïve PD-1−/− mice displayed elevated Th1 and Th17 levels, but diminished Th2 cytokine levels, ligation of PD-1 limited cytokine production by in vitro-polarized Th1 and Th17 cells, but slightly enhanced cytokine production by in vitro-polarized Th2 cells, and PD-1 ligation enhanced Th2 cytokine production by naïve T cells cultured under non-polarizing conditions. These data demonstrate that different CD4+ T cell subsets respond differentially to PD-1 ligation and may explain some of the variable results observed in control of allergic asthma by the PD-1 family members. As the PD-1/PD-L1 axis limits asthma severity by constraining Th17 cell activity, this suggests that severe allergic asthma may be associated with a defective PD-1/PD-L1 regulatory axis in some individuals.

Interleukin 12 (IL-12)-mediated Type 1 inflammation confers host-protection against the parasitic protozoan Toxoplasma gondii. However, production of interferon gamma (IFN-γ), another Type 1 inflammatory cytokine, also drives lethality from excessive injury to the intestinal epithelium. As mechanisms that restore epithelial barrier function following infection remain poorly understood, this study investigated the role of Trefoil factor 2 (TFF2), a well-established regulator of mucosal tissue repair. Paradoxically, TFF2 antagonized IL-12 release from DC’s and macrophages, which protected TFF2 deficient mice (TFF2−/−) from T. gondii pathogenesis. Dysregulated intestinal homeostasis in naïve TFF2−/− mice correlated with increased IL-12/23p40 levels and enhanced T cell recruitment at baseline. Infected TFF2−/− mice displayed low rates of parasite replication and reduced gut immunopathology, whereas WT mice experienced disseminated infection and lethal ileitis. p38 MAPK activation and IL-12p70 production was more robust from TFF2−/− CD8+ DC compared to WT CD8+ DC and treatment of WT DC with rTFF2 suppressed TLR-induced IL-12/23p40 production. Neutralization of IFN-γ and IL-12 in TFF2−/− animals abrogated resistance shown by enhanced parasite replication and infection-induced morbidity. Hence, TFF2 regulated intestinal barrier function and Type 1 cytokine release from myeloid phagocytes, which dictated the outcome of oral T. gondii infection in mice.

Up to a third of the world's population is infected with Toxoplasma gondii. Natural infection in humans can be life threatening during pregnancy and in immunocompromised individuals. Toll-like receptor (TLR) 11 is the mouse innate sensor that recognizes T. gondii profilin; however, in humans the TLR11 gene leads to transcription of no functional protein. Herein, by using a multiple sequence alignment phylogenetic analysis program between human and mouse species, we found that human TLR5 seems to be the evolutionarily closest member of the TLR gene family to mouse tlr11. We therefore asked whether human TLR5 could mediate IL-6, IL-8 and IL-12p70 production in response to the T. gondii profilin. We found that this was the case both in human cell lines as well as peripheral blood monocytes. Moreover, TLR5 neutralization and gene silencing mediated specific ablation of cytokine production after profilin exposure. Finally, peripheral blood monocytes carrying the TLR5 R392X mutation failed to produce cytokines in response to stimulation with profilin. Taken together, the results presented herein reveal a previously unappreciated cross-recognition of a relevant human pathogen-derived pathogen-associated molecular pattern.

Foundation; and the Sunshine Charitable Foundation and its supporters, Denise A. Bunning and David G. Bunning and the Mary H Weiser Food Allergy Center. Disclosure of potential conflict of interest: V. Mukkada is a consultant and receives research funding from Shire. M. E. Rothenberg is a consultant for PulmOne, Spoon Guru, ClostraBio, Celgene, Shire, AstraZeneca, GlaxoSmithKline, Allakos, Adare, Regeneron, and Novartis and has an equity interest in the first 4 listed and Immune Pharmaceuticals and receives royalties from reslizumab (Teva Pharmaceuticals) and UpToDate; he is also an inventor of patents owned by Cincinnati Children's Hospital Medical Center. S. P. Hogan is an inventor of patents owned by Cincinnati Children's Hospital Medical Center. The rest of the authors declare that they have no relevant conflicts of interest.

No abstract

Transforming growth factor β (TGF-β) regulates inflammation, immunosuppression, and wound-healing cascades, but it remains unclear whether any of these functions involve regulation of myeloid cell function. The present study demonstrates that selective deletion of TGF-βRII expression in myeloid phagocytes i) impairs macrophage-mediated suppressor activity, ii) increases baseline mRNA expression of proinflammatory chemokines/cytokines in the lung, and iii) enhances type 2 immunity against the hookworm parasite Nippostrongylus brasiliensis. Strikingly, TGF-β-responsive myeloid cells promote repair of hookworm-damaged lung tissue, because LysM(Cre)TGF-βRII(flox/flox) mice develop emphysema more rapidly than wild-type littermate controls. Emphysematous pathology in LysM(Cre)TGF-βRII(flox/flox) mice is characterized by excessive matrix metalloprotease (MMP) activity, reduced lung elasticity, increased total lung capacity, and dysregulated respiration. Thus, TGF-β effects on myeloid cells suppress helminth immunity as a consequence of restoring lung function after infection.