Endo-Lysosomes and Antigen Presentation

For phagocytic immune cells, endosomes and lysosomes are critical organelles. Endosomes transport samples of extracellular material into the cell and eventually fuse with lysosomes to create the endo-lysosomal compartment. In this compartment antigens are processed and loaded onto Major Histocompatibility Complex II (MHC-II) molecules for subsequent antigen presentation to T cells. Although classically recognized as waste-management organelles, in pathogen-stimulated dendritic cells (DC) these degradative abilities are dampened to preserve peptides. In addition to functional changes, endo-lysosomes also transform from globular organelles into far-reaching tubular networks. While endo-lysosomes appear to play a key role in antigen presentation, the mechanisms driving these structural and functional changes remain poorly understood.

A recent publication by Hipolito et al. sought to elucidate the molecular underpinnings of this dynamic endo-lysosomal response. In this study, primary murine phagocytes stimulated with the bacterial protein lipopolysaccharide (LPS) showed rapid remodeling of the endo-lysosome, increasing the volume and holding capacity of this compartment after just two hours. This expansion was associated with increased levels of six lysosome-associated proteins, but not their corresponding messenger RNAs (mRNA).

The authors thus examined post-transcriptional mechanisms that may contribute to endo-lysosome expansion, focusing on mammalian target of rapamycin complex 1 (mTORC1). In addition to stimulating mRNA translation, previous literature has shown that mTORC1 is activated in LPS-stimulated macrophages and is necessary for endo-lysosomal tubulation. Hipolito and colleagues found that mTORC1 also plays a role in endo-lysosome expansion and lysosomal-protein translation as these processes were diminished in cells treated with the mTORC1 inhibitor torin1. Additionally, RNA sequencing analysis of an LPS-stimulated macrophage cell line showed activation or inhibition of mTORC1 lead to differences in mRNA translational efficiencies. This suggests mTORC1 may mediate other functional changes within the endo-lysosome.

To understand the impact of mTORC1 on antigen presentation the authors used antibody staining to visualize MHC-II:peptide complexes in torin1-treated DCs stimulated with LPS. Cells with active mTORC1 showed increased MHC-II:peptide complexes as wells as increased MHC-II protein levels compared to cells where mTORC1 activity was inhibited. Additionally, only DCs with active mTORC1 were capable of stimulating IL-2 secretion from T-cells, suggesting that mTORC1 may be important to T-cell activation.

Literature in the innate immunology field largely focuses on changes in cell metabolism, transcription, and cytokine production following pathogen exposure. This study demonstrates that cellular infrastructure is also critical in coordinating appropriate immune responses. mTORC1-modulated endo-lysosome expansion may allow phagocytes to retain more extracellular cargo for antigen processing and tubulation may facilitate delivery of MHC-II:peptide complexes to the cell surface for presentation to T cells. While mTORC1 has been implicated in metabolic reprogramming and managing inflammatory responses in activated innate immune cells, this study points to a role for mTORC1 in endo-lysosome remodeling and potentially antigen secretion. Thus, mTORC1 appears to have multiple interesting and independent functions in immune cell activation. The impact of endo-lysosome restructuring on antigen presentation represents an underappreciated feature of immunity, and additional research in this area may offer novel strategies for harnessing mechanisms of the human immune system to fight infection.