αv Integrins regulate germinal center B cell responses through noncanonical autophagy.
αv Integrins regulate germinal center B cell responses through noncanonical autophagy.
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αv 整合素通过非典型自噬调节生发中心 B 细胞反应。
DOI：
10.1172/jci99597
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Acharya,Mridu
中科院分区：
文献类型：
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作者：
Raso,Fiona;Sagadiev,Sara;Du,Samuel;Gage,Emily;Arkatkar,Tanvi;Metzler,Genita;Stuart,LyndaM;Orr,MarkT;Rawlings,DavidJ;Jackson,ShaunW;Lacy-Hulbert,Adam;Acharya,Mridu
生殖中心（GC）是克隆B细胞扩增和产生对病原体的长寿命、高亲和力抗体应答的主要场所。通过B细胞上的TLR的信号传导促进GC B细胞应答的许多方面，包括亲和力成熟、类别转换和分化为长寿记忆细胞和浆细胞。有效疫苗接种的主要挑战是确定特异性促进GC B细胞应答的策略。在这里，我们已经确定了GC B细胞TLR信号的调节机制，由α v整合素和非经典自噬介导。使用B细胞特异性αv-KO小鼠，我们发现α v介导的TLR调节的丧失增加了GC B细胞扩增、体细胞超变、类别转换和用病毒样颗粒（VLP）或与TLR配体佐剂相关的抗原免疫后长寿命浆细胞的产生。此外，靶向α v介导的调节增加了对流感病毒疫苗接种的抗体应答的幅度和广度。因此，这些数据确定了GC B细胞的调节机制，其可以被靶向以增强对疫苗接种的抗体应答。
Germinal centers (GCs) are major sites of clonal B cell expansion and generation of long-lived, high-affinity antibody responses to pathogens. Signaling through TLRs on B cells promotes many aspects of GC B cell responses, including affinity maturation, class switching, and differentiation into long-lived memory and plasma cells. A major challenge for effective vaccination is identifying strategies to specifically promote GC B cell responses. Here, we have identified a mechanism of regulation of GC B cell TLR signaling, mediated by αvintegrins and noncanonical autophagy. Using B cell–specific αv-KO mice, we show that loss of αv-mediated TLR regulation increased GC B cell expansion, somatic hypermutation, class switching, and generation of long-lived plasma cells after immunization with virus-like particles (VLPs) or antigens associated with TLR ligand adjuvants. Furthermore, targeting αv-mediated regulation increased the magnitude and breadth of antibody responses to influenza virus vaccination. These data therefore identify a mechanism of regulation of GC B cells that can be targeted to enhance antibody responses to vaccination.