Macropinocytosis drives T cell growth by sustaining the activation of mTORC1

Charpentier, John C.; Chen, Di; Lapinski, Philip E.; Turner, Jackson S.; Grigorova, Irina; Swanson, Joel A.; King, Philip D.

doi:10.1038/s41467-019-13997-3

Cited by 54 publications

(44 citation statements)

References 34 publications

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“…As for B cells, T cells have not traditionally been considered candidates for active macropinocytosis. However, recently, both primary mouse and human CD4 + and CD8 + T cells have been shown to exhibit significant basal levels of macropinocytosis and, moreover, the basal levels are increased upon cell activation [68]. Treatment with EIP-amiloride not only blocks macropinocytosis by non-activated and activated T cells, but also reduces mTORC1 activation and T cell growth [68].…”

Section: B Cells and T Cellsmentioning

confidence: 99%

“…However, recently, both primary mouse and human CD4 + and CD8 + T cells have been shown to exhibit significant basal levels of macropinocytosis and, moreover, the basal levels are increased upon cell activation [68]. Treatment with EIP-amiloride not only blocks macropinocytosis by non-activated and activated T cells, but also reduces mTORC1 activation and T cell growth [68]. These findings suggest a model whereby macropinocytosis mediates uptake of amino acids required for activation of mTORC1 and as a result, growth of T cells [68].…”

Section: B Cells and T Cellsmentioning

confidence: 99%

“…Treatment with EIP-amiloride not only blocks macropinocytosis by non-activated and activated T cells, but also reduces mTORC1 activation and T cell growth [68]. These findings suggest a model whereby macropinocytosis mediates uptake of amino acids required for activation of mTORC1 and as a result, growth of T cells [68]. Macropinocytosis has also been implicated in the uptake of single-stranded antisense oligonucleotides flanked by locked nucleic acids (LNAs), called GapmeR, to successfully knockdown genes in primary human T cells [69].…”

Section: B Cells and T Cellsmentioning

confidence: 99%

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Macropinocytosis in Different Cell Types: Similarities and Differences

2020

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Macropinocytosis is a unique pathway of endocytosis characterised by the nonspecific internalisation of large amounts of extracellular fluid, solutes and membrane in large endocytic vesicles known as macropinosomes. Macropinocytosis is important in a range of physiological processes, including antigen presentation, nutrient sensing, recycling of plasma proteins, migration and signalling. It has become apparent in recent years from the study of specialised cells that there are multiple pathways of macropinocytosis utilised by different cell types, and some of these pathways are triggered by different stimuli. Understanding the physiological function of macropinocytosis requires knowledge of the regulation and fate of the macropinocytosis pathways in a range of cell types. Here, we compare the mechanisms of macropinocytosis in different primary and immortalised cells, identify the gaps in knowledge in the field and discuss the potential approaches to analyse the function of macropinocytosis in vivo.

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Section: B Cells and T Cellsmentioning

confidence: 99%

Section: B Cells and T Cellsmentioning

confidence: 99%

Section: B Cells and T Cellsmentioning

confidence: 99%

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Macropinocytosis in Different Cell Types: Similarities and Differences

2020

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“…However, the majority of PA binding that we measured was likely due to macropinocytosis. Recent studies have demonstrated that non-professional phagocytes, such as B cells and T cells, also perform macropinocytosis [82,83]. Therefore, it is likely that NK cells and NKT cells can also sample their environment via this internalization mechanism.…”

Section: Discussionmentioning

confidence: 99%

Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes

Patel

Booth

Dozmorov

et al. 2020

Toxins

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Bacillus anthracis, the causative agent of inhalation anthrax, is a serious concern as a bioterrorism weapon. The vegetative form produces two exotoxins: Lethal toxin (LT) and edema toxin (ET). We recently characterized and compared six human airway and alveolar-resident phagocyte (AARP) subsets at the transcriptional and functional levels. In this study, we examined the effects of LT and ET on these subsets and human leukocytes. AARPs and leukocytes do not express high levels of the toxin receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). Less than 20% expressed surface TEM8, while less than 15% expressed CMG2. All cell types bound or internalized protective antigen, the common component of the two toxins, in a dose-dependent manner. Most protective antigen was likely internalized via macropinocytosis. Cells were not sensitive to LT-induced apoptosis or necrosis at concentrations up to 1000 ng/mL. However, toxin exposure inhibited B. anthracis spore internalization. This inhibition was driven primarily by ET in AARPs and LT in leukocytes. These results support a model of inhalation anthrax in which spores germinate and produce toxins. ET inhibits pathogen phagocytosis by AARPs, allowing alveolar escape. In late-stage disease, LT inhibits phagocytosis by leukocytes, allowing bacterial replication in the bloodstream.

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“…Macropinocytosis can be stimulated by growth factors in many cell types 110 , yet can be constitutive in RAS-mutant cancer cells 117 and some subsets of MΦ 118 and DCs 110 . Macropinocytosis mediates immune cell functions such as antigen scavenging and presentation by MΦ and DCs 118 , chemotactic migration of neutrophils 119 , and proliferation of T cells 120 . Macropinocytosis in particular has been shown to mediate uptake of nanomaterials, including lipid nanoparticles (LNPs) 121 and silica-based nanoparticles 122 .…”

Section: Mechanisms Of Materials Uptake By Phagocytesmentioning

confidence: 99%

Macrophage imaging and subset analysis using single-cell RNA sequencing

Arlauckas

Weissleder

et al. 2021

Nanotheranostics

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Macrophages have been associated with drug response and resistance in diverse settings, thus raising the possibility of using macrophage imaging as a companion diagnostic to inform personalized patient treatment strategies. Nanoparticle-based contrast agents are especially promising because they efficiently deliver fluorescent, magnetic, and/or radionuclide labels by leveraging the intrinsic capacity of macrophages to accumulate nanomaterials in their role as professional phagocytes. Unfortunately, current clinical imaging modalities are limited in their ability to quantify broad molecular programs that may explain (a) which particular cell subsets a given imaging agent is actually labeling, and (b) what mechanistic role those cells play in promoting drug response or resistance. Highly multiplexed single-cell approaches including single-cell RNA sequencing (scRNAseq) have emerged as resources to help answer these questions. In this review, we query recently published scRNAseq datasets to support companion macrophage imaging, with particular focus on using dextran-based nanoparticles to predict the action of anti-cancer nanotherapies and monoclonal antibodies.

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Macropinocytosis drives T cell growth by sustaining the activation of mTORC1

Cited by 54 publications

References 34 publications

Macropinocytosis in Different Cell Types: Similarities and Differences

Macropinocytosis in Different Cell Types: Similarities and Differences

Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes

Macrophage imaging and subset analysis using single-cell RNA sequencing

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