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The IL-21 receptor (IL-21R) shows significant homology with the IL-4R, and CD4+ Th2 cells are an important source of IL-21. Here we examined whether the IL-21R regulates the development of Th2 responses in vivo. To do this, we infected IL-21R-/- mice with the Th2-inducing pathogens Schistosoma mansoni and Nippostrongylus brasiliensis and examined the influence of IL-21R deficiency on the development of Th2-dependent pathology. We showed that granulomatous inflammation and liver fibrosis were significantly reduced in S. mansoni-infected IL-21R-/- mice and in IL-21R+/+ mice treated with soluble IL-21R-Fc (sIL-21R–Fc). The impaired granulomatous response was also associated with a marked reduction in Th2 cytokine expression and function, as evidenced by the attenuated IL-4, IL-13, AMCase, Ym1, and FIZZ1 (also referred to as RELMα) responses in the tissues. A similarly impaired Th2 response was observed following N. brasiliensis infection. In vitro, IL-21 significantly augmented IL-4Rα and IL-13Rα1 expression in macrophages, resulting in increased FIZZ1 mRNA and arginase-1 activity following stimulation with IL-4 and IL-13. As such, these data identify the IL-21R as an important amplifier of alternative macrophage activation. Collectively, these results illustrate an essential function for the IL-21R in the development of pathogen-induced Th2 responses, which may have relevance in therapies for both inflammatory and chronic fibrotic diseases.

Alternatively activated (M2) macrophages use fatty acid oxidation for their metabolic needs. Pearce and colleagues show that triacylglycerols metabolized by lysosomal acid lipase are required for the M2 activation of and function of macrophages. Alternative (M2) activation of macrophages driven via the α-chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.

The role of neutrophils in helminth infection has been relatively unclear. Gause and colleagues demonstrate that neutrophils are involved in the priming of an M2 macrophage response that mediates long-term protection against helminth infection. We examined the role of innate cells in acquired resistance to the natural murine parasitic nematode, Nippostrongylus brasiliensis . Macrophages obtained from lungs as late as 45 d after N. brasiliensis inoculation were able to transfer accelerated parasite clearance to naive recipients. Primed macrophages adhered to larvae in vitro and triggered increased mortality of parasites. Neutrophil depletion in primed mice abrogated the protective effects of transferred macrophages and inhibited their in vitro binding to larvae. Neutrophils in parasite-infected mice showed a distinct transcriptional profile and promoted alternatively activated M2 macrophage polarization through secretory factors including IL-13. Differentially activated neutrophils in the context of a type 2 immune response therefore prime a long-lived effector macrophage phenotype that directly mediates rapid nematode damage and clearance.

Key Points Helminth parasites cause chronic disease in billions of people, however, the immune response associated with helmith infection can also reduce the severity of certain harmful inflammatory autoimmune and allergic diseases. Studies of tissue-dwelling parasites in murine models reveal the development of T helper 2 (T H 2)-type granulomas consisting of cellular infiltrates that resemble T H 1-type granulomas; however, the cells are activated differently and have distinct functions. The T H 2-type response can affect host protection by mediating helminth expulsion or by controlling otherwise pathological inflammatory responses that are driven by T H 1 and T H 17 cells. T H 2 cells are the primary source of T H 2-type cytokines but innate cells can also produce these cytokines. T H 2-type cytokines, including interleukin-4 (IL-4) and IL-13, orchestrate a potent T H 2-type response by direct stimulation of both bone-marrow-derived and non-bone-marrow-derived cell populations. A similarly complex and multi-faceted T H 2-type response is elicited following infection with a wide variety of helminths; however, only certain components of this broad response are effective against a particular species. The discovery of new effector cell types and molecules contributing to the host protective T H 2-type response provides additional targets for the development of novel therapies against helminths. Helminths infect millions of people worldwide. In this Review, William Gause and colleagues outline the current understanding of immune responses against helminth infections, focusing on results obtained in mouse models of infection with Heligmosomoides polygyrus and Schistosoma mansoni . Important insights have recently been gained in our understanding of how host immune responses mediate resistance to parasitic helminths and control associated pathological responses. Although similar cells and cytokines are evoked in response to infection by helminths as diverse as nematodes and schistosomes, the components of the response that mediate protection are dependent on the particular parasite. In this Review, we examine recent findings regarding the mechanisms of protection in helminth infections that have been elucidated in murine models and discuss the implications of these findings in terms of future therapies.

Although primary and memory responses against bacteria and viruses have been studied extensively, T helper type 2 (TH2) effector mechanisms leading to host protection against helminthic parasites remain elusive1. Examination of the intestinal epithelial submucosa of mice after primary and secondary infections by a natural gastrointestinal parasite revealed a distinct immune-cell infiltrate after challenge, featuring interleukin-4-expressing memory CD4+ T cells that induced IL-4 receptorhi (IL-4Rhi) CD206+ alternatively activated macrophages2. In turn, these alternatively activated macrophages (AAMacs) functioned as important effector cells of the protective memory response contributing to parasite elimination, demonstrating a previously unknown mechanism for host protection against intestinal helminths.

Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla(-/-) mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla(-/-) mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla(-/-) mice infected with the gastrointestinal (GI) parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla(-/-) mice developed stronger Th2 responses, which could be reversed by exogenous rRelmalpha treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-gamma, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses.

The physiological function of the mammalian chitinase AMCase is unclear. Wynn and colleagues show that it is dispensable for allergic lung inflammation but is necessary for clearance of intestinal helminths. Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri . The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13 , Chil3 , Retnlb , and Clca1 . CD103 + dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.

The interleukin 4 receptor (IL-4R) is a central mediator of T helper type 2 (TH2-mediated disease and associates with either the common γ-chain to form the type I IL-4R or with the IL-13R α1 chain (IL-13Rα1) to form the type II IL-4R. Here we used Il13ra1- /- mice to characterize the distinct functions of type I and type II IL-4 receptors in vivo. In contrast to Il4ra- /- mice, which have weak TH2 responses, Il13ra1- /- mice had exacerbated TH2 responses. Il13ra1- /- mice showed much less mortality after infection with Schistosoma mansoni and much more susceptibility to Nippostrongylus brasiliensis. IL-13Rα1 was essential for allergen-induced airway hyperreactivity and mucus hypersecretion but not for fibroblast or alternative macrophage activation. Thus, type I and II IL-4 receptors exert distinct effects on immune responses.

Trichuriasis, caused by the parasitic nematode Trichuris trichiura , remains a major public health concern, particularly in resource-limited regions. Current anthelmintics show suboptimal efficacy against whipworm infections, highlighting the critical need for novel therapeutic strategies. This study provides a comparative framework by integrating transcriptional profiles from in vivo and in vitro models during the early infection phase of T. muris , a mouse model for T. trichiura . Through this approach, we demonstrate the potential of proximal colonoids as a model for investigating key aspects of host–parasite interactions, including epithelial invasion and transcriptional dynamics, during early T. muris infection. By employing dual-RNA sequencing, we not only characterize temporal gene expression dynamics of first-stage larvae but also identify host–parasite co-expression profiles, thereby shedding light on molecular pathways that may underlie infection establishment and host responses. This work builds upon and solidifies previous findings about the utility of organoid models for investigating early whipworm infection while providing a foundational resource for exploring intervention strategies targeting the initial stages of infection.

Expression of the transcription factor GATA-3 is strongly associated with T helper type 2 (T H 2) differentiation, but genetic evidence for its involvement in this process has been lacking. Here, we generated a conditional GATA-3-deficient mouse line. In vitro deletion of Gata3 diminished both interleukin 4 (IL-4)–dependent and IL-4-independent T H 2 cell differentiation; without GATA-3, T H 1 differentiation occurred in the absence of IL-12 and interferon-γ. Gata3 deletion limited the growth of T H 2 cells but not T H 1 cells. Deletion of Gata3 from established T H 2 cells abolished IL-5 and IL-13 but not IL-4 production. In vivo deletion of Gata3 using OX40-Cre eliminated T H 2 responses and allowed the development of interferon-γ-producing cells in mice infected with Nippostrongylus brasiliensis . Thus, GATA-3 serves as a principal switch in determining T H 1-T H 2 responses.