Journal
CELLS
Volume 11, Issue 23, Pages -Publisher
MDPI
DOI: 10.3390/cells11233883
Keywords
B cell; antigen extraction; TLR; CpG; autophagy; alpha V integrin; LPS
Categories
Funding
- NIH
- Proyecto Fondecyt [R01AI151167]
- ANID/Doctorado Nacional Chile [1180900]
- [2016-21161495]
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TLR stimulation induces autophagy in B cells and decreases their capacity to extract and present immobilized antigens. This is achieved by triggering autophagy-dependent degradation of GEF-H1, which restricts lysosome repositioning to the immune synapse. The degradation of GEF-H1 is not observed in B cells deficient in TLR-induced autophagy.
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 alpha V 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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