B cell receptor and Toll-like receptor signaling coordinate to control distinct B-1 responses to both self and the microbiota.

Lieselotte Sm Kreuk,Leianna C Slayden,Gregory M Barton,Meghan A Koch,Sophia Chu,Nicholas A Lind,Nicole Baumgarth,Hannah P Savage,Aaron B Kantor

doi:10.7554/elife.47015

Lieselotte Sm Kreuk, Leianna C Slayden + Show 7 more

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https://doi.org/10.7554/elife.47015

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Abstract

B-1a cells play an important role in mediating tissue homeostasis and protecting against infections. They are the main producers of 'natural' IgM, spontaneously secreted serum antibodies predominately reactive to self antigens, like phosphatidylcholine (PtC), or antigens expressed by the intestinal microbiota. The mechanisms that regulate the B-1a immunoglobulin (Ig) repertoire and their antibody secretion remain poorly understood. Here, we use a novel reporter mouse to demonstrate that production of self- and microbiota-reactive antibodies is linked to BCR signaling in B-1a cells. Moreover, we show that Toll-like receptors (TLRs) are critical for shaping the Ig repertoire of B-1a cells as well as regulating their antibody production. Strikingly, we find that both the colonization of a microbiota as well as microbial-sensing TLRs are required for anti-microbiota B-1a responses, whereas nucleic-acid sensing TLRs are required for anti-PtC responses, demonstrating that linked activation of BCR and TLRs controls steady state B-1a responses to both self and microbiota-derived antigens.

Highlights

B-1a cells were discovered 35 years ago and have characteristics that bridge the innate and adaptive immune system (Herzenberg et al, 1986)
We considered the possibility that the Ighg3T2A-Cre: TdTomato mouse marks a subset of activated B-1a cells and that activation of these cells correlates with induction of the Ighg3 germ-line transcript (GLT) rather than class switch recombination (CSR) to IgG3
The significantly higher expression of the BCR-downstream signaling gene Nur77 in splenic versus peritoneal cavity B-1a cells combined with the enrichment of BCR reactivities to both PtC and the intestinal microbiota in the Tomato+ activated subset of splenic B-1a cells from reporter mice strongly suggests a BCR-mediated expansion process

Summary

Introduction

B-1a cells were discovered 35 years ago and have characteristics that bridge the innate and adaptive immune system (Herzenberg et al, 1986). B-1a cells are the main producers of serum IgM antibodies (Lalor et al, 1989a; Baumgarth et al, 1999; Ohdan et al, 2000; Haas et al, 2005; Choi and Baumgarth, 2008; Holodick et al, 2009), which promote tissue homeostasis and provide protection against infections (Haas et al, 2005; Choi and Baumgarth, 2008; Boes et al, 1998; Ochsenbein et al, 1999; Boes et al, 2000; Ehrenstein et al, 2000; Baumgarth et al, 2000; Alugupalli et al, 2003; Notley et al, 2011; Vas et al, 2013). The most common B-1a specificity is for phosphatidylcholine (PtC), a phospholipid present within the plasma membranes of eukaryotic cells

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