Showing papers by "Edward J. Pearce published in 2015"

Dendritic cell metabolism.

Abstract: The past 15 years have seen enormous advances in our understanding of the receptor and signalling systems that allow dendritic cells (DCs) to respond to pathogens or other danger signals and initiate innate and adaptive immune responses. We are now beginning to appreciate that many of these pathways not only stimulate changes in the expression of genes that control DC immune functions, but also affect metabolic pathways, thereby integrating the cellular requirements of the activation process. In this Review, we focus on this relatively new area of research and attempt to describe an integrated view of DC immunometabolism.

Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

Abstract: Parasitic helminth worms, such as Schistosoma mansoni, are endemic in regions with a high prevalence of tuberculosis (TB) among the population. Human studies suggest that helminth coinfections contribute to increased TB susceptibility and increased rates of TB reactivation. Prevailing models suggest that T helper type 2 (Th2) responses induced by helminth infection impair Th1 immune responses and thereby limit Mycobacterium tuberculosis (Mtb) control. Using a pulmonary mouse model of Mtb infection, we demonstrated that S. mansoni coinfection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1–expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity. In a genetically diverse mouse population infected with Mtb, enhanced arginase-1 activity was associated with increased lung inflammation. Moreover, in patients with pulmonary TB, lung damage correlated with increased serum activity of arginase-1, which was elevated in TB patients coinfected with helminths. Together, our data indicate that helminth coinfection induces arginase-1–expressing type 2 granulomas, thereby increasing inflammation and TB disease severity. These results also provide insight into the mechanisms by which helminth coinfections drive increased susceptibility, disease progression, and severity in TB.

IL-4–Secreting Secondary T Follicular Helper (Tfh) Cells Arise from Memory T Cells, Not Persisting Tfh Cells, through a B Cell–Dependent Mechanism

Abstract: Humoral immunity requires cross-talk between T follicular helper (Tfh) cells and B cells. Nevertheless, a detailed understanding of this intercellular interaction during secondary immune responses is lacking. We examined this by focusing on the response to a soluble, unadjuvanted, pathogen-derived Ag (soluble extract of Schistosoma mansoni egg [SEA]) that induces type 2 immunity. We found that activated Tfh cells persisted for long periods within germinal centers following primary immunization. However, the magnitude of the secondary response did not appear to depend on pre-existing Tfh cells. Instead, Tfh cell populations expanded through a process that was dependent on memory T cells recruited into the reactive LN, as well as the participation of B cells. We found that, during the secondary response, IL-4 was critical for the expansion of a population of plasmablasts that correlated with increased SEA-specific IgG1 titers. Additionally, following immunization with SEA (but not with an Ag that induced type 1 immunity), IL-4 and IL-21 were coproduced by individual Tfh cells, revealing a potential mechanism through which appropriate class-switching can be coupled to plasmablast proliferation to enforce type 2 immunity. Our findings demonstrate a pivotal role for IL-4 in the interplay between T and B cells during a secondary Th2 response and have significant implications for vaccine design.

The metabolic control of schistosome egg production.

Abstract: Schistosomiasis is a neglected tropical disease caused by infection with trematode parasites of the genus Schistosoma Despite ongoing treatment programmes, the prevalence of schistosomiasis has failed to decline and the disease remains a cause of severe morbidity in millions of people Understanding the biology of egg production by schistosomes is critical since eggs allow transmission of the infection, and when trapped in host tissues induce the immune responses that are responsible for the pathologic changes that underlie disease development Unusually among trematodes, adult schistosomes exhibit sexual dimorphism and display a fascinating codependency in that the female is dependent on the male to grow and sexually mature Thus, virgin females are developmentally stunted compared with females from mixed-sex infections and are unable to lay eggs Moreover, fecund female schistosomes rapidly lose the ability to produce eggs when placed in tissue culture Here we discuss the metabolic regulation of egg production in schistosomes, and in particular the critical role played by fatty acid oxidation in this process