Infection with parasitic helminths can imprint the immune system to modulate bystander inflammatory processes. Bystander or virtual memory CD8+ T cells (TVM) are non-conventional T cells displaying memory properties that can be generated through responsiveness to interleukin (IL)-4. However, it is not clear if helminth-induced type 2 immunity functionally affects the TVM compartment. Here, we show that helminths expand CD44hiCD62LhiCXCR3hiCD49dlo TVM cells through direct IL-4 signaling in CD8+ T cells. Importantly, helminth-mediated conditioning of TVM cells provided enhanced control of acute respiratory infection with the murid gammaherpesvirus 4 (MuHV-4). This enhanced control of MuHV-4 infection could further be explained by an increase in antigen-specific CD8+ T cell effector responses in the lung and was directly dependent on IL-4 signaling. These results demonstrate that IL-4 during helminth infection can non-specifically condition CD8+ T cells, leading to a subsequently raised antigen-specific CD8+ T cell activation that enhances control of viral infection.

Alternatively activated Mϕs (AAMϕ) accumulate in hepatic granulomas during schistosomiasis and have been suggested to originate in the bone marrow. What is less understood is how these Mϕ responses are regulated after S. mansoni infection. Here, we investigated the role of IL-4 receptor α-chain (IL-4Rα)-signalling in the dynamics of liver Mϕ responses. We observed that IL-4Rα signalling was dispensable for the recruitment of Ly6C hi monocytes and for their conversion into F4/80 hi CD64 hi CD11b hi Mϕ. Moreover, while IL-4Rα provided an AAMϕ phenotype to liver F4/80 hi CD64 hi CD11b hi Mϕ that was associated with regulation of granuloma formation, it was dispensable for host survival. Resident F4/80 hi CD64 hi CD11b lo Mϕ did not upregulate the AAMϕ signature gene Ym1. Rather, resident Mϕ nearly disappeared by week 8 after infection and artificial ablation of resident Mϕ in CD169 DTR mice did not affect the response to S. mansoni infection. Interestingly, ablation of CD169 + cells in naive mice resulted in the accumulation of F4/80 hi CD64 hi CD11b hi Mϕ, which was amplified when ablation occurred during schistosomiasis. Altogether, our results suggest the ablation of resident KCs after S. mansoni infection to be associated with the recruitment and accumulation of F4/80 hi CD64 hi CD11b hi Mϕ with lyz2-dependent IL-4Rα contributing to the regulation of granuloma inflammation but being dispensable for host survival.Keywords: liver r monocytes r mouse model r Mϕ r schistosomiasis See accompanying Commentary by Rückerl and CookAdditional supporting information may be found online in the Supporting Information section at the end of the article. infected with Schistosoma mansoni develop a severe liver pathology with granulomatous inflammatory responses directed toward the parasite eggs. During chronic infections, type 2 inflammation in the liver results in fibrosis, which leads to portal hypertension, bleeding from collateral vessels and ultimately death [2][3][4]. Mϕ accumulate in the liver and are a key cellular component in granuloma formation and host protection [2,5].Mϕ are plastic cells that can be alternatively activated by IL-4 and IL-13 via the type I or type II IL-4 receptor, respectively [6].

Macrophages are highly plastic innate immune cells that adopt an important diversity of phenotypes in response to environmental cues. Helminth infections induce strong type 2 cell-mediated immune responses, characterized among other things by production of high levels of interleukin- (IL-) 4 and IL-13. Alternative activation of macrophages by IL-4 in vitro was described as an opposite phenotype of classically activated macrophages, but the in vivo reality is much more complex. Their exact activation state as well as the role of these cells and associated molecules in type 2 immune responses remains to be fully understood. We can take advantage of a variety of helminth models available, each of which have their own feature including life cycle, site of infection, or pathological mechanisms influencing macrophage biology. Here, we reviewed the recent advances from the laboratory mouse about macrophage origin, polarization, activation, and effector functions during parasitic helminth infection.

Maternal immune transfer is the most significant source of protection from early-life infection, but whether maternal transfer of immunity by nursing permanently alters offspring immunity is poorly understood. Here, we identify maternal immune imprinting of offspring nursed by mothers who had a pre-conception helminth infection. Nursing of pups by helminth-exposed mothers transferred protective cellular immunity to these offspring against helminth infection. Enhanced control of infection was not dependent on maternal antibody. Protection associated with systemic development of protective type 2 immunity in T helper 2 (TH2) impaired IL-4Rα−/− offspring. This maternally acquired immunity was maintained into maturity and required transfer (via nursing) to the offspring of maternally derived TH2-competent CD4 T cells. Our data therefore reveal that maternal exposure to a globally prevalent source of infection before pregnancy provides long-term nursing-acquired immune benefits to offspring mediated by maternally derived pathogen-experienced lymphocytes.

Highlights d Optimized electroporation of cRNP complexes in primary mature innate immune cells d High knockout efficiency of signaling adaptors and transcription factors d cRNP-mediated knockout of Stat4 in primary NK cells during MCMV infection d cRNP knockout reveals MyD88 is required for cDC1dependent control of MCMV infection

Innate lymphoid cells (ILCs) are tissue-resident sentinels of the immune system that function to protect local tissue microenvironments against pathogens and maintain homeostasis. However, because ILCs are sensitively tuned to perturbations within tissues, they can also contribute to host pathology when critical activating signals become dysregulated. Recent work has demonstrated that the crosstalk between ILCs and their environment has a significant impact on host metabolism in health and disease. In this review, we summarize studies that support evidence for the ability of ILCs to influence tissue and systemic metabolism, as well as how ILCs can be regulated by environmental changes in systemic host metabolism. We also highlight studies demonstrating how ILC- intrinsic metabolism influences their activation, proliferation, and homeostasis. Finally, this review discusses the challenges and open questions in the rapidly expanding field of ILCs and immunometabolism.

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