A p38α-BLIMP1 signalling pathway is essential for plasma cell differentiation

Jianfeng Wu, Kang Yang, Shaowei Cai, Xiaohan Zhang, Lichen Hu, Fanjia Lin, Su-qin Wu, Changchun Xiao, Wen-Hsien Liu () and Jiahuai Han ()
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Jianfeng Wu: Xiamen University
Kang Yang: Xiamen University
Shaowei Cai: Xiamen University
Xiaohan Zhang: Xiamen University
Lichen Hu: Xiamen University
Fanjia Lin: Xiamen University
Su-qin Wu: Xiamen University
Changchun Xiao: Xiamen University
Wen-Hsien Liu: Xiamen University
Jiahuai Han: Xiamen University

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Plasma cells (PC) are antibody-secreting cells and terminal effectors in humoral responses. PCs differentiate directly from activated B cells in response to T cell-independent (TI) antigens or from germinal center B (GCB) cells in T cell-dependent (TD) antigen-induced humoral responses, both of which pathways are essentially regulated by the transcription factor BLIMP1. The p38 mitogen-activated protein kinase isoforms have already been implicated in B cell development, but the precise role of p38α in B cell differentiation is still largely unknown. Here we show that PC differentiation and antibody responses are severely impaired in mice with B cell-specific deletion of p38α, while B cell development and the GCB cell response are spared. By utilizing a Blimp1 reporter mouse model, we show that p38α-deficiency results in decreased BLIMP1 expression. p38α-driven BLIMP1 up-regulation is required for both TI and TD PCs differentiation. By combining CRISPR/Cas9 screening and other approaches, we identify TCF3, TCF4 and IRF4 as downstream effectors of p38α to control PC differentiation via Blimp1 transcription. This study thus identifies an important signalling pathway underpinning PC differentiation upstream of BLIMP1, and points to a highly specialized and non-redundant role for p38α among p38 isoforms.

Date: 2022
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DOI: 10.1038/s41467-022-34969-0

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