Autophagy Induced by Toll-like Receptor Ligands Regulates Antigen Extraction and Presentation by B Cells

Abstract

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.

Endolysosomal vesicles at the center of B cell activation

“…In line with this, another study reported the accumulation of LC3 with the internalized antigen (Runsala et al, 2023), together indicating that autophagy-linked protein machinery is activated in response to B cell IS formation and involved in targeting the internalized antigen for further processing. Interestingly, tolllike receptor ligands, such as lipopolysaccharide (LPS), restrict lysosome repositioning to the IS of B cells by triggering autophagy-dependent degradation of GEF-H1, a Rho GTP exchange factor required for stable lysosome recruitment at the synaptic membrane (Lagos et al, 2022). The BCR activation state can regulate the autophagic signature in a manner dependent on the cell stage and the local microenvironment: it was recently proposed that a switch from mTORC1-driven canonical to noncanonical autophagy occurs in the germinal center (GC) B cells upon B cell activation, proposing that the B cell stage and location in situ may influence the responses to antigen exposure via alternating the autophagy route (Martinez-Martin et al, 2017;Raza and Clarke, 2021).…”