BCAP Regulates Dendritic Cell Maturation Through the Dual-Regulation of NF-κB and PI3K/AKT Signaling During Infection.

Yuhui Miao,Lu Qi,Ming Jiang,Weihua Xiao,Fang Fang,De Yang

doi:10.3389/fimmu.2020.00250

Abstract

The maturation of dendritic cells (DCs) is essential in adaptive immunity. B cell adapter for phosphoinositide 3-kinase (BCAP) has been shown a divergent activities in cell type dependent manner including B cells, NK cells, macrophages, and plasmacytoid DCs (pDCs), however, its role in conventional DCs (cDCs) remains unknown. Here, we report that BCAP negatively regulates Toll-like receptor-induced cDC maturation and inhibits cDCs from inducing antigen-specific T cell responses, thereby weakening the antibacterial adaptive immune responses of mice in a Listeria monocytogenes-infection model. Furthermore, we demonstrate that BCAP simultaneously modulates the activation of the NF-κB and PI3K/AKT signaling by dynamically interacting with, respectively, MyD88 and the p85α subunit of PI3K. Our study thus reveals non-redundant roles for BCAP in regulating cDC maturation and reveals a bilateral signal transduction mechanism.

Highlights

dendritic cells (DCs) bridge innate immunity and adaptive immunity through their unique antigen-presenting ability [1, 2]
DTx administration resulted in the clearance of CD11c+ conventional DCs (cDCs) from CD11c-DTR bone marrow rather than plasmacytoid DCs (pDCs) or CD11c+ macrophages in these mixed bone marrow chimeras (Figure S1A), and the residual cDCs were mainly derived from WT bone marrow (CD11cDTR/WT→ CD45.1 chimeras) or B cell adapter for phosphoinositide 3-kinase (BCAP)-deficient bone marrow (CD11c-DTR/BCAP-KO→ CD45.1 chimeras)
The Listeria monocytogenes expressing ovalbumin (LM-OVA) burden was much lower than CD11cDTR/WT→ CD45.1 chimeras in the spleens (Figure 1B) rather than in the livers (Figure 1C) of CD11c-DTR/BCAP-KO→ CD45.1 chimeras, suggesting that BCAP deficiency in cDCs resulted in reduced susceptibility to LM-OVA in mice

Summary

Introduction

DCs bridge innate immunity and adaptive immunity through their unique antigen-presenting ability [1, 2]. A normal maturation of DCs is indispensable for the establishment of powerful innate and adoptive immune responses during infection, and abnormal maturation of DCs is often linked with immune disorders and diseases. While excessive maturation of DCs leads to transplant rejection and the onset of autoimmune disease [5, 6], loss of normal DC maturation results in uncontrollable infection and inflammation. It has become clear that immature DCs mainly elicit immunological tolerance and are critical for the establishment of peripheral tolerance [5, 7, 8], which further underlines the critical role of mature DCs in shaping appropriate adaptive immune responses

Methods

Results

Conclusion