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

Ryota Higuchi; Kaori Tanaka; Yuichi Saito; Daisuke Murakami; Takashi Nakagawa; Stephen L Nutt; Yasuyuki Ohkawa; Yoshihiro Baba

doi:10.1093/pnasnexus/pgae152

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. eCollection 2024 Apr.

Authors

Ryota Higuchi^{1

2}, Kaori Tanaka³, Yuichi Saito², Daisuke Murakami², Takashi Nakagawa², Stephen L Nutt^{4

5}, Yasuyuki Ohkawa³, Yoshihiro Baba¹

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.

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.