Investigating the importance of B cells and antibodies during Trichuris muris infection using the IgMi mouse

Abstract

The IgMi mouse has normal B cell development; its B cells express an IgM B cell receptor but cannot class switch or secrete antibody. Thus, the IgMi mouse offers a model system by which to dissect out antibody-dependent and antibody-independent B cell function. Here, we provide the first detailed characterisation of the IgMi mouse post-Trichuris muris (T. muris) infection, describing expulsion phenotype, cytokine production, gut pathology and changes in T regulatory cells, T follicular helper cells and germinal centre B cells, in addition to RNA sequencing (RNA seq) analyses of wild-type littermates (WT) and mutant B cells prior to and post infection. IgMi mice were susceptible to a high-dose infection, with reduced Th2 cytokines and elevated B cell-derived IL-10 in mesenteric lymph nodes (MLN) compared to controls. A low-dose infection regime revealed IgMi mice to have significantly more apoptotic cells in the gut compared to WT mice, but no change in intestinal inflammation. IL-10 levels were again elevated. Collectively, this study showcases the potential of the IgMi mouse as a tool for understanding B cell biology and suggests that the B cell plays both antibody-dependent and antibody-independent roles post high- and low-dose T. muris infection. Key messages During a high-dose T. muris infection, B cells are important in maintaining the Th1/Th2 balance in the MLN through an antibody-independent mechanism. High levels of IL-10 in the MLN early post-infection, and the presence of IL-10-producing B cells, correlates with susceptibility to T. muris infection. B cells maintain gut homeostasis during chronic T. muris infection via an antibody-dependent mechanism.

Context-dependent roles of B cells during intestinal helminth infection

“…Although the roles of Bregs are primarily demonstrated in experimental schistosomiasis, mice lacking the B cells that fail to class-switch their IgM to any other isotypes and are unable to secrete antibodies (IgMi −/− mice) have identified an interesting connection of Bregs to susceptibility and gut immunopathology following T. muris infection [108]. In contrast to schistosomiasis, the resistance to T. muris infection requires Th2-biased responses without the need for a balanced Th response between Th1 and Th2 components [109].…”

“…In contrast to schistosomiasis, the resistance to T. muris infection requires Th2-biased responses without the need for a balanced Th response between Th1 and Th2 components [109]. The susceptibility of IgMi −/− mice towards a supposedly resolving acute infection is associated with IL-10 production by B cells during early stages of infection, with dysregulated Th2 responses at later time points of infection [108]. Conversely, in the chronic setting of T. muris infection, the intestinal crypts of IgMi −/− mice had increased apoptotic cells, with elevated IL-10 production by B cells [108].…”

“…The susceptibility of IgMi −/− mice towards a supposedly resolving acute infection is associated with IL-10 production by B cells during early stages of infection, with dysregulated Th2 responses at later time points of infection [108]. Conversely, in the chronic setting of T. muris infection, the intestinal crypts of IgMi −/− mice had increased apoptotic cells, with elevated IL-10 production by B cells [108]. This indicates that antibodies but not B cell-derived IL-10 are in part responsible for worm clearance and maintaining gut homeostasis during acute and chronic T. muris infection, respectively.…”

“…By contrast, there is no effective immunity to primary H. polygyrus infection in C57BL/6 mice that can result in a sterile immunity [112], and thus the absence of B cells and antibodies does not influence the susceptibility; however, they can promote intestinal repair [132]. Conversely, μMT −/− mice [17,74], B cell-depleted mice via anti-CD20 treatment [17,74], and mice that are unable to secrete any soluble antibodies (IgMi −/− mice) [108] all fail to protect the host during primary T. muris infection (Table 2). Furthermore, J H D −/− mice had impaired worm expulsion and increased fecal eggs in response to primary Strongyloides venezuelensis infection [133].…”

“…Antibody-mediated worm expulsion during primary response [108] IgE-deficient mice (IgE −/− ) Nippostrongylus brasiliensis, Trichinella spiralis IgE −/− mice retain the ability to remain resistant to primary infection.…”