Autophagy Induced by Toll-like Receptor Ligands Regulates Antigen Extraction and Presentation by B Cells.
Autophagy Induced by Toll-like Receptor Ligands Regulates Antigen Extraction and Presentation by B Cells.
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作者：
B细胞与表面束缚抗原的结合触发免疫突触(IS)的形成，其中溶酶体的局部分泌可以促进抗原摄取。溶酶体与其他细胞内过程相交，如Toll样受体(TLR)信号和自噬协调免疫反应。然而，这些过程和抗原呈递之间的串扰仍然不清楚。在这里，我们发现TLR刺激诱导了B细胞的自噬，降低了它们提取和呈递固定化抗原的能力。我们揭示，TLR刺激通过触发依赖自噬的全球环境基金-H1的降解来限制溶酶体对IS的重新定位。环境基金-H1是一种Rho GTP交换因子，需要在突触膜上稳定地招募溶酶体。在缺乏αV整合素和缺乏TLR诱导的自噬的B细胞中，没有观察到全环基金-H1的降解。因此，这些细胞在TLR刺激下表现出有效的抗原提取，证实了TLR诱导的自噬在限制抗原提取中的作用。总体而言，我们的结果表明，与自噬相关的资源调节TLR和BCR依赖的功能，这可以微调B细胞摄取抗原。这项工作有助于理解B细胞在抗原识别之前被表面束缚的抗原激活的机制，例如败血症。
The engagement of B cells with surface-tethered antigens triggers the formation of an immune synapse (IS), where the local secretion of lysosomes can facilitate antigen uptake. Lysosomes intersect with other intracellular processes, such as Toll-like Receptor (TLR) signaling and autophagy coordinating immune responses. However, the crosstalk between these processes and antigen presentation remains unclear. Here, we show that TLR stimulation induces autophagy in B cells and decreases their capacity to extract and present immobilized antigens. We reveal that TLR stimulation restricts lysosome repositioning to the IS by triggering autophagy-dependent degradation of GEF-H1, a Rho GTP exchange factor required for stable lysosome recruitment at the synaptic membrane. GEF-H1 degradation is not observed in B cells that lack αV integrins and are deficient in TLR-induced autophagy. Accordingly, these cells show efficient antigen extraction in the presence of TLR stimulation, confirming the role of TLR-induced autophagy in limiting antigen extraction. Overall, our results suggest that resources associated with autophagy regulate TLR and BCR-dependent functions, which can finetune antigen uptake by B cells. This work helps to understand the mechanisms by which B cells are activated by surface-tethered antigens in contexts of subjacent inflammation before antigen recognition, such as sepsis.
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影响因子：
32.4
作者：
Hou B;Saudan P;Ott G;Wheeler ML;Ji M;Kuzmich L;Lee LM;Coffman RL;Bachmann MF;DeFranco AL
通讯作者：
DeFranco AL
DOI：
10.1084/jem.20110640
发表时间：
2011-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ireland JM;Unanue ER
通讯作者：
Unanue ER
影响因子：
7.2
作者：
Harwood, Naomi E.;Batista, Facundo D.
通讯作者：
Batista, Facundo D.
在长期持久性中自噬的需求，而不是记忆B细胞的初始形成。
DOI：
10.4049/jimmunol.1403001
发表时间：
2015-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chen M;Kodali S;Jang A;Kuai L;Wang J
通讯作者：
Wang J
早期的BCR事件和B细胞上MHC II类上的抗原捕获，加工和加载。
影响因子：
7.3
作者：
Avalos AM;Ploegh HL
通讯作者：
Ploegh HL