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

Kathryn J Else,Werner Muller,Iris Mair,Ruth Forman,Emma A Murphy,Muhammad Z H Fadlullah,Ari Waisman,Rinal Sahputra

doi:10.1007/s00109-020-01954-3

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 messagesDuring 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.

Highlights

Worm infections affect about one third of the population worldwide with most infected people suffering chronic infections and carrying worms asymptomatically for the rest of their lives [1, 2]
We investigated IL-10 production within the B1a, B1b, follicular zone (FO) and marginal zone (MZ) B cell subsets
FoxP3+CD25+ T regulatory (Treg) were significantly increased in mesenteric lymph nodes (MLN) and spleen of IgMi mice at day 10 p.i., intracellular staining confirmed that B cells were the main cellular source of IL-10 in IgMi mice at day 10 p.i

Summary

Introduction

Worm infections affect about one third of the population worldwide with most infected people suffering chronic infections and carrying worms asymptomatically for the rest of their lives [1, 2]. T. muris infections in mice have been used to study T. trichiura in man to uncover mechanisms of protective immunity [3]. After α-CD20 monoclonal antibody-mediated B cell depletion, Th2 responses were reduced in the MLN of C57BL/6 mice which were unable to expel the parasite [5]. Depletion of B cells using αCD20 monoclonal antibodies is a useful tool in dissecting out the importance of B cells in infection, but it does not discriminate between the multiple possible roles played by the B cell post infection. As an alternative strategy to understanding the important role played by the B cell in resistance to T. muris, B cell-mutant mice can be used [6]

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Conclusion