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IL-21R 信号重编程与 CD40 和 BCR 信号协同作用，选择和分化生发中心 B 细胞。

IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells.

机构信息

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.

Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.

出版信息

Sci Immunol. 2023 Feb 24;8(80):eadd1823. doi: 10.1126/sciimmunol.add1823. Epub 2023 Feb 17.

DOI:10.1126/sciimmunol.add1823
PMID:36800413
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10206726/
Abstract

Both B cell receptor (BCR) and CD40 signaling are rewired in germinal center (GC) B cells (GCBCs) to synergistically induce c-MYC and phosphorylated S6 ribosomal protein (p-S6), markers of positive selection. How interleukin-21 (IL-21), a key T follicular helper (T)-derived cytokine, affects GCBCs is unclear. Like BCR and CD40 signals, IL-21 receptor (IL-21R) plus CD40 signals also synergize to induce c-MYC and p-S6 in GCBCs. However, IL-21R plus CD40 stimulation differentially affects GCBC fate compared with BCR plus CD40 ligation-engaging unique molecular mechanisms-as revealed by bulk RNA sequencing (RNA-seq), single-cell RNA-seq, and flow cytometry of GCBCs in vitro and in vivo. Whereas both signal pairs induced BLIMP1 in some GCBCs, only the IL-21R/CD40 combination induced IRF4/CD138 cells, indicative of plasma cell differentiation, along with CCR6/CD38 memory B cell precursors. These findings reveal a second positive selection pathway in GCBCs, document rewired IL-21R signaling in GCBCs, and link specific T- and Ag-derived signals to GCBC differentiation.

摘要

B 细胞受体 (BCR) 和 CD40 信号在生发中心 (GC) B 细胞 (GCBC) 中被重新布线，以协同诱导 c-MYC 和磷酸化 S6 核糖体蛋白 (p-S6)，这是阳性选择的标志物。白细胞介素-21 (IL-21)，一种关键的滤泡辅助 T 细胞 (Tfh) 衍生细胞因子，如何影响 GCBC 尚不清楚。像 BCR 和 CD40 信号一样，IL-21 受体 (IL-21R) 加 CD40 信号也协同诱导 GCBC 中的 c-MYC 和 p-S6。然而，与 BCR 加 CD40 交联相比，IL-21R 加 CD40 刺激对 GCBC 命运的影响不同，这是通过体外和体内 GCBC 的批量 RNA 测序 (RNA-seq)、单细胞 RNA-seq 和流式细胞术揭示的独特分子机制。虽然这两种信号对都在一些 GCBC 中诱导了 BLIMP1，但只有 IL-21R/CD40 组合诱导了 IRF4/CD138 细胞，表明浆细胞分化，同时还诱导了 CCR6/CD38 记忆 B 细胞前体。这些发现揭示了 GCBC 中的第二个阳性选择途径，记录了 GCBC 中重新布线的 IL-21R 信号，并将特定的 T 细胞和抗原衍生信号与 GCBC 分化联系起来。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05e1/10206726/16b15d08f4cb/nihms-1887587-f0007.jpg
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