Abstract
Toll like receptors (TLRs) induced response plays a vital role in B-cell development and activation, in which TLR7-mediated and TLR9-mediated response interact together and play antagonistic or cooperative roles at different situations. Previous studies showed that the transcription factor signal transducer and activator of transcription (STAT) 3 was one of the key transcriptional factors (TFs) needed for both TLR7 and TLR9 signaling in B cell, and patients with autosomal dominant hyper IgE syndromes (AD-HIES) due to STAT3 mutations having defective TLRs response in B cells. However, how STAT3 affects its target genes and the downstream signaling pathways in B cell upon TLRs stimulation remains unclarified on a genome-wide level. ChIP-seq and RNA-seq was used in this study to identify the STAT3 targets in response to TLRs stimulation in human B cell. STAT3 ChIP-seq results showed a total of 611 and 2,289 differential STAT3-binding sites in human B cell after TLR7 and TLR9 agonists stimulation, respectively. RNA-seq results showed 1,186 and 1,775 differentially expressed genes after TLR7 and TLR9 activation, respectively. We identified 47 primary STAT3 target genes after TLR7 activation and 189 target genes after TLR9 activation in B cell by integration of STAT3 ChIP-seq and RNA-seq data. Among these STAT3 primary targets, we identified 7 TFs and 18 TFs for TLR7 and TLR9 response, respectively. Besides, we showed that STAT3 might regulate TLR9, but not TLR7 response in B cells through directly regulating integrin signaling pathway, which might further affect the antagonism between TLR7 and TLR9 signaling in B cell. Our study provides insights into the molecular mechanism of human TLRs response in B cell and how it can be regulated, which helps to better understand and modulate TLR-mediated pathogenic immune responses in B cell.
Highlights
Bcell plays a central role in adaptive immunity, whose activation is tightly controlled by four kinds of receptors that include B cell receptors (BCRs), cytokine receptors, receptors involved in cognate T cell–B cell interactions, and innate immune receptors, namely, Toll-like receptors (TLRs) [1–3]
The results showed that Toll like receptors (TLRs) induced phosphorylation of STAT3 in human B cell, and the STAT3 phosphorylation induced by R848 was faster than that induced by CpG
We showed that STAT3 might regulate TLR9, but not TLR7 response in B cells through directly regulating integrin signaling pathway, further affecting the antagonism between TLR7 and TLR9 signaling in B cells
Summary
Bcell plays a central role in adaptive immunity, whose activation is tightly controlled by four kinds of receptors that include B cell receptors (BCRs), cytokine receptors, receptors involved in cognate T cell–B cell interactions, and innate immune receptors, namely, Toll-like receptors (TLRs) [1–3]. In the past decades, accumulating pieces of evidence has demonstrated the importance of TLRs in the B-cell development and activation, and their role in the pathogenesis of autoimmune disease and Bcell malignancies [1–4]. Human B cell mainly express the endosomal TLR7 and TLR9 that are involved in the recognition of RNA and DNA from microbial-derived nucleic acid or endogenous nucleic acid released from damaged or dying cells, respectively [3, 5]. Aberrant activation of B cell incited by excessive endogenous nucleic acid released by damaged or dying cells could lead to the generation of autoantibodies, and subsequent autoimmune diseases. Aberrant TLRs activation in B cell was reported in patients with primary immunodeficient diseases, such as hyper-IgE syndrome (HIES) [6, 7] and common variable immunodeficiency disease (CVID) [5, 8], and autoimmune diseases, namely, systemic lupus erythematosus (SLE) and Sjögren’s syndrome [9, 10]
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