The Extracellular Domains of IgG1 and T Cell-Derived IL-4/IL-13 Are Critical for the Polyclonal Memory IgE Response In Vivo.

Adriana Turqueti-Neves,Oliver Pabst,Manuel Otte,Michaela Erika Renate Schmitt,Cornelia Lindner,David Voehringer,Philipp Yu,Christian Schwartz,David Nemazee

doi:10.1371/journal.pbio.1002290

Abstract

IgE-mediated activation of mast cells and basophils contributes to protective immunity against helminths but also causes allergic responses. The development and persistence of IgE responses are poorly understood, which is in part due to the low number of IgE-producing cells. Here, we used next generation sequencing to uncover a striking overlap between the IgE and IgG1 repertoires in helminth-infected or OVA/alum-immunized wild-type BALB/c mice. The memory IgE response after secondary infection induced a strong increase of IgE+ plasma cells in spleen and lymph nodes. In contrast, germinal center B cells did not increase during secondary infection. Unexpectedly, the memory IgE response was lost in mice where the extracellular part of IgG1 had been replaced with IgE sequences. Adoptive transfer studies revealed that IgG1+ B cells were required and sufficient to constitute the memory IgE response in recipient mice. T cell-derived IL-4/IL-13 was required for the memory IgE response but not for expansion of B cells from memory mice. Together, our results reveal a close relationship between the IgE and IgG1 repertoires in vivo and demonstrate that the memory IgE response is mainly conserved at the level of memory IgG1+ B cells. Therefore, targeting the generation and survival of allergen-specific IgG1+ B cells could lead to development of new therapeutic strategies to treat chronic allergic disorders.

Highlights

IgE probably emerged during mammalian evolution to defend hosts against parasites, since a correlation between high IgE levels and protection against helminths has been recognized [1,2]
Allergic inflammation is initiated when IgE antibodies bind to high-affinity receptors on the cell surface of mast cells and basophils, thereby triggering the release of proinflammatory mediators
We first treated cells isolated from the draining lymph nodes (LN) with an acidic wash buffer to remove cytophilic IgE bound to the low affinity IgE receptor FcεRII (CD23) and stained for surface and intracellular IgE and IgG1

Summary

Introduction

IgE probably emerged during mammalian evolution to defend hosts against parasites, since a correlation between high IgE levels and protection against helminths has been recognized [1,2]. Class switch recombination (CSR) to IgE is induced by IL-4 or IL-13-mediated activation of STAT6. We recently discovered that STAT6 expression in B cells was required for germinal center (GC) formation in response to helminth infection and during allergic inflammation [9]. Infection of mice with the gastrointestinal helminth Nippostrongylus brasiliensis is a well-established model to study general mechanisms of IgE production in vivo. Serum IgE levels of N. brasiliensis-infected BALB/c mice increase up to 1,000-fold by day 14 after N. brasiliensis infection [10]. Th2 cells and TFH cells are generally considered to be the most relevant cell types for induction of IgE-CSR in B cells, it remains unclear to what extent innate IL-4/IL-13-expressing cell types contribute to this process, especially during secondary infection when basophils and mast cells can be rapidly activated to release large amounts of IL-4/IL-13

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