Alternative (M2) macrophage activation driven through interleukin 4 receptor α (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 fatty acids to support this metabolic program has not been clear. We show that the uptake of triacylglycerol substrates via CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation (OXPHOS), 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 against this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.

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.More than two billion people are infected with parasitic helminths 1 . Although infections by these pathogens are generally not fatal, they are associated with high rates of morbidity, with chronic infection often leading to anaemia and malnourishment 1 . Developed countries have controlled these infections through primary health-care programmes and effective public sanitation, but helminth diseases are still widespread in developing nations and often drug treatment does not protect against rapid re-infection. The need for effective vaccines to control these infections is compelling and at least a few clinical trials are currently underway 2,3 ; however, one impediment towards development of an effective vaccine is a lack of understanding of the actual components of the immune response that mediate protection against helminths. In this Review, we examine the host protective mechanisms with regard to the cell types and molecules involved in helminth expulsion and in control of pathological inflammation that is associated with infection.Helminth infections and the corresponding host immune responses are products of a prolonged dynamic co-evolution between the host and parasite. For parasites, it is advantageous to trick the host into developing an ineffective immune response, to find a suitable niche for maturation and propagation, and to do so without killing or unduly harming the host. Conversely, the host NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript has to ideally generate an effective immune response to expel the parasite, and minimize its harmful effects, while not sacrificing its ability to effectively respond to other pathogens. The host immune system evolved in the context of a parasite-replete environment, and the balance of immune effector and regulatory cell populations are at least partly a consequence of ongoing responses to infectious organisms that can often simultaneously invade host tissues. Although such dynamic host-pathogen interactions exist throughout much of the world, in industrialized countries infectious diseases are better controlled as a result of increased hygiene, the administration of vaccines at an early age and the widespread use of antibiotics. Although this has resulted in marked reductions in chronic and severe disease, recent studies indicate a possible adverse effect of this enhanced control of infectious diseases that...

Innate lymphoid cells (ILCs) are lymphocyte-like cells lacking T or B cell receptors that mediate protective and repair functions through cytokine secretion. Among them, type 2 ILC (ILC2) cells are capable of producing type 2 cytokines. We report the existence of an inflammatory (i) ILC2 population responsive to IL-25 that complements IL-33-responsive natural (n) ILC2 cells. iILC2 cells developed into nILC2-like cells in vitro and in vivo, contributing to expulsion of Nippostrongylus brasiliensis. They also acquired IL-17-producing capacity, providing partial protection against Candida albicans. We propose that iILC2 cells are transient ILC progenitors mobilized by inflammation and infection that develop into nILC2-like cells or ILC3-like cells and contribute to immunity to both helminths and fungi.

Although primary and memory responses against bacteria and viruses have been studied extensively, T helper type 2 (T H 2) effector mechanisms leading to host protection against helminthic parasites remain elusive 1 . 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 receptor hi (IL-4R hi ) CD206 + alternatively activated macrophages 2 . 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.Productive adaptive immune responses result in CD4 + T-cell polarization into effector phenotypes defined by differing cytokine milieus 3 . Helminth parasites and allergens induce T H 2 responses, including CD4 + T-cell interleukin (IL)-4 production promoting arginase-1 expression by alternatively activated macrophages (AAMacs) 4 . Although it is known that these AAMacs accumulate during asthmatic inflammation 5 and helminth parasite infections 2,4,6, 7 , and downregulate type 1 inflammation 2,4,6 , a protective role for them remains undefined.Infection of mice with the natural mouse gastrointestinal helminth parasite Heligmosomoides polygyrus triggers a highly polarized T H 2 response 1 . H. polygyrus infection is chronic with established adult worms; if parasites are cleared from the host's intestinal lumen, a rapid, protective T H 2 memory response operates against challenge infections 8 . Our studies examined early events in this memory response to H. polygyrus larvae developing in the intestinal submucosa and indicated that AAMacs have an important role in parasite expulsion. Fig. 1 online), with tissue-invading larvae developing into adults and migrating into the lumen at day 8 after inoculation ( Supplementary Fig. 1). To examine which stages of the protective memory response required CD4 + T cells, we administered CD4-specific antibody to mice to deplete CD4 + cells at specific intervals after secondary infection (Fig. 1a). Administration at early time points (days 0 and 7) resulted in increased worm burden (Fig. 1b), day 7 treatment had intermediate effects, and later treatments (days 9 or 11) had marginal effects, indicating that CD4 + T cells are required at early stages of a secondary infection for effective parasite expulsion. This implicated the adaptive immune response during larval development in the intestinal tissue as crucial for host protection. To further confirm that the memory response affects invasive larvae, we recovered muscularis-residing larvae from infected small intestines by using a Baermann apparatus 9 , which provokes premature larval evacuation of the tissue, as an indicator of health and mobility. Significantly fewer larvae were recovered from the tissues of m...