CD1d-dependent immune suppression mediated by regulatory B cells through modulations of iNKT cells

K Oleinika,C Mauri,E C Rosser,K Nistala,I Drozdov,A Bosma,D E Matei

doi:10.1038/s41467-018-02911-y

Abstract

Regulatory B cells (Breg) express high levels of CD1d that presents lipid antigens to invariant natural killer T (iNKT) cells. The function of CD1d in Breg biology and iNKT cell activity during inflammation remains unclear. Here we show, using chimeric mice, cell depletion and adoptive cell transfer, that CD1d–lipid presentation by Bregs induces iNKT cells to secrete interferon (IFN)-γ to contribute, partially, to the downregulation of T helper (Th)1 and Th17-adaptive immune responses and ameliorate experimental arthritis. Mice lacking CD1d-expressing B cells develop exacerbated disease compared to wild-type mice, and fail to respond to treatment with the prototypical iNKT cell agonist α-galactosylceramide. The absence of lipid presentation by B cells alters iNKT cell activation with disruption of metabolism regulation and cytokine responses. Thus, we identify a mechanism by which Bregs restrain excessive inflammation via lipid presentation.

Highlights

Regulatory B cells (Breg) express high levels of CD1d that presents lipid antigens to invariant natural killer T cells
To address the role that B cells play in α-GalCer-invariant natural killer T (iNKT) cell-driven amelioration of arthritis, B cell-deficient and WT mice were immunized to induce arthritis and treated with α-GalCer. α-GalCer treatment suppressed the development of arthritis in WT mice, while it failed to inhibit the disease in μMT mice (Fig. 1a)
While the upregulation of MHC class II molecules upon B cell activation promotes the activation of CD4+ helper T cells, CD1d-dependent presentation of α-GalCer by B cells to iNKT cells generates an activation signal that drives antibody production[18,19,46,47,48]

Summary

Introduction

Regulatory B cells (Breg) express high levels of CD1d that presents lipid antigens to invariant natural killer T (iNKT) cells. The function of CD1d in Breg biology and iNKT cell activity during inflammation remains unclear. INKT cells are involved in the enhancement of antitumor immunity, protection against infections, and regulation of autoimmunity[10]. In the latter context, administration of αgalactosylceramide (α-GalCer), the prototypical iNKT cell glycolipid agonist, has been shown to suppress the development of autoimmunity in mice[11,12,13]. We have shown that B cells from SLE patients with active disease express decreased levels of CD1d and do not support the expansion and activation of iNKT cells upon in vitro stimulation with α-GalCer[1]

Methods

Results

Conclusion