Abstract
Signals controlling the generation of regulatory B (Breg) cells remain ill-defined. Here we report an "auto"-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells. In healthy individuals, pDCs drive the differentiation of CD19(+)CD24(hi)CD38(hi) (immature) B cells into IL-10-producing CD24(+)CD38(hi) Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement. CD24(+)CD38(hi) Breg cells conversely restrained IFN-α production by pDCs via IL-10 release. In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells. This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α. Defective pDC-mediated expansion of CD24(+)CD38(hi) Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24(+)CD38(hi) Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24(+)CD38(hi) Breg cell interaction contributes to the pathogenesis of SLE.
Original language | English |
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Pages (from-to) | 683-697 |
Number of pages | 15 |
Journal | Immunity |
Volume | 44 |
Issue number | 3 |
DOIs | |
Publication status | Published - 15 Mar 2016 |
Keywords
- Adult
- Aged
- Antigens, CD/metabolism
- Antirheumatic Agents/administration & dosage
- B-Lymphocytes, Regulatory/drug effects
- Cell Communication/drug effects
- Cell Differentiation/drug effects
- Cells, Cultured
- Dendritic Cells/drug effects
- Female
- Homeostasis/drug effects
- Humans
- Interferon-gamma/metabolism
- Interleukin-10/metabolism
- Lupus Erythematosus, Systemic/drug therapy
- Male
- Middle Aged
- Rituximab/administration & dosage
- STAT1 Transcription Factor/metabolism
- STAT3 Transcription Factor/metabolism
- Transcriptional Activation/drug effects
- Young Adult