2. Academic Validation
  3. Type I interferon promotes the fate of Toll-like receptor 9-stimulated follicular B cells to plasma cell differentiation

Type I interferon promotes the fate of Toll-like receptor 9-stimulated follicular B cells to plasma cell differentiation

  • PNAS Nexus. 2024 Apr 17;3(4):pgae152. doi: 10.1093/pnasnexus/pgae152.
Ryota Higuchi 1 2,  Kaori Tanaka 3,  Yuichi Saito 2,  Daisuke Murakami 2,  Takashi Nakagawa 2,  Stephen L Nutt 4 5,  Yasuyuki Ohkawa 3,  Yoshihiro Baba 1
Affiliations

Affiliations

  • 1 Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
  • 2 Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
  • 3 Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
  • 4 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3050, Australia.
  • 5 Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
PMID: 38659975 DOI: 10.1093/pnasnexus/pgae152
Abstract

The activation and differentiation of B cells into plasma cells (PCs) play critical roles in the immune response to infections and autoimmune diseases. Toll-like Receptor 9 (TLR9) responds to Bacterial and viral DNA containing unmethylated CpG motifs and triggers immune responses in B cells; however, abnormal recognition of self-DNA by TLR9 can cause autoimmune diseases. When stimulated with TLR9 agonists, follicular (FO) B cells, a subset of B cells residing in the FO regions of secondary lymphoid organs, exhibit a propensity for activation but fail to give rise to PCs. The factors that enable the transition of TLR9-activated FO B cells from activation to differentiation into PCs remain unclear. In this study, we show that type I interferon-alpha (IFNα) signaling causes FO B cells activated by CpG stimulation to differentiate into PCs. Although CpG stimulation alone only temporarily increased interferon regulatory factor 4 (IRF4) expression in FO B cells, co-stimulation with both CpG and IFNα enhanced and maintained high IRF4 expression levels, ultimately enabling the cells to differentiate into PCs. Overexpression of IRF4 in FO B cells results in CpG-induced PC transition without IFN signaling. Furthermore, co-stimulation of TLR9 and IFNα receptors significantly enhanced mammalian target of rapamycin (mTOR) signaling, which regulates IRF4 expression and PC generation. These findings suggest that IFNα may play a key role in promoting the fate of PC differentiation in FO B cells activated by TLR9 stimulation.

Keywords

B cells; IRF4; TLR9; plasma cells; type 1 IFN.

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