A septin requirement differentiates autonomous and contact-facilitated T cell proliferation

Mujal, Adriana M.; Gilden, Julia; Gérard, Audrey; Kinoshita, Makoto; Krummel, Matthew F.

doi:10.1038/ni.3330

Cited by 23 publications

(21 citation statements)

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“…An important link between the innate and the adaptive immune system consists of cytokine-induced maturation of dendritic cells which in turn initiate the adaptive immune response [ 15 , 16 ]. Although not completely understood, it can be hypothesized that T cell proliferation based on a generally activated immunological environment is more prominent than selective stimulation of proliferation pathways [ 17 , 18 ]. One major limitation of imaging as biomarker is the lack of cellular resolution in comparison to FACS analysis.…”

Section: Discussionmentioning

confidence: 99%

In vivo imaging of the immune response upon systemic RNA cancer vaccination by FDG-PET

et al. 2018

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Background[18F]Fluoro-2-deoxy-2-d-glucose positron emission tomography (FDG-PET) is commonly used in the clinic for diagnosis of cancer and for follow-up of therapy outcome. Additional to the well-established value in tumor imaging, it bears potential to depict immune processes in modern immunotherapies. T cells enhance their glucose consumption upon activation and are crucial effectors for the success of such novel therapies. In this study, we analyzed the T cell immunity in spleen after antigen-specific stimulation of T cells via highly innovative RNA-based vaccines using FDG-PET/MRI. For this purpose, we employed systemic administration of RNA-lipoplexes encoding the endogenous antigen of Moloney murine leukemia virus (gp70) which have been previously shown to induce potent innate as well as adaptive immune mechanisms for cancer immunotherapy. Feasibility of clinical imaging of increased splenic FDG uptake was demonstrated in a melanoma patient participating in a clinical phase 1 trial of a tetravalent RNA-lipoplex cancer vaccine.ResultsWe observed exclusive increase of glucose uptake in spleen compared to other organs thanks to liposome-mediated RNA targeting to this immune-relevant organ. In vivo and ex vivo FDG uptake analysis in the spleen of vaccinated mice correlated well with antigen-specific T cell activation. Moreover, the use of an irrelevant (antigen non-specific) RNA also resulted in enhanced FDG uptake early after vaccination through the activation of several other splenic cell populations. The glucose uptake was also dependent on the dose of RNA administered in line with the activation and frequencies of proliferating antigen-specific T cells as well as the general activation pattern of splenic cell populations.ConclusionsOur preclinical results show rapid and transient vaccination-induced increase of FDG uptake within the spleen reflecting immune activation preceding T cell proliferation. FDG-PET/CT in patients is also capable to image this immune activation resulting in a new potential application of FDG-PET/CT to image immune processes in new immunological therapies.Electronic supplementary materialThe online version of this article (10.1186/s13550-018-0435-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

In vivo imaging of the immune response upon systemic RNA cancer vaccination by FDG-PET

et al. 2018

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“…For example, knockout of SEPT7 blocks cell division in fibroblasts but not in lymphocytes (Sellin et al, 2011; Menon et al, 2014). T-lymphocytes in contact with other cells do not require septins for division, whereas single T cells that are not in contact with other cells depend on septins for cell division (Mujal et al, 2016). …”

Section: Septins Regulate Socementioning

confidence: 99%

Regulation of Store-Operated Ca2+ Entry by Septins

Deb

Hasan

2016

Front. Cell Dev. Biol.

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The mechanism of store-operated Ca2+ entry (SOCE) brings extracellular Ca2+ into cells after depletion of intracellular Ca2+ stores. Regulation of Ca2+ homeostasis by SOCE helps control various intracellular signaling functions in both non-excitable and excitable cells. Whereas essential components of the SOCE pathway are well characterized, molecular mechanisms underlying regulation of this pathway need investigation. A class of proteins recently demonstrated as regulating SOCE is septins. These are filament-forming GTPases that assemble into higher order structures. One of their most studied cellular functions is as a molecular scaffold that creates diffusion barriers in membranes for a variety of cellular processes. Septins regulate SOCE in mammalian non-excitable cells and in Drosophila neurons. However, the molecular mechanism of SOCE-regulation by septins and the contribution of different subgroups of septins to SOCE-regulation remain to be understood. The regulation of SOCE is relevant in multiple cellular contexts as well as in diseases, such as the Severe Combined Immunodeficiency (SCID) syndrome and neurodegenerative syndromes like Alzheimer's, Spino-Cerebellar Ataxias and Parkinson's. Moreover, Drosophila neurons, where loss of SOCE leads to flight deficits, are a possible cellular template for understanding the molecular basis of neuronal deficits associated with loss of either the Inositol-1,4,5-trisphosphate receptor (IP3R1), a key activator of neuronal SOCE or the Endoplasmic reticulum resident Ca2+ sensor STIM1 (Stromal Interaction Molecule) in mouse. This perspective summarizes our current understanding of septins as regulators of SOCE and discusses the implications for mammalian neuronal function.

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“…Septins have been identified as the “cell‐division cycle” proteins, and they play a critical role during cytokinesis . It has been reported that septins are indispensable in co‐ordinating myosin motor proteins and bind with non‐muscle myosin II to activate myosin II in interphase and dividing cells and reorganizingx membrane during cytokinesis, and anchoring the midbody ring structure in the membrane when a daughter cell separates from its mother cell.…”

Section: Introductionmentioning

confidence: 99%

“…15,16 Septins have been identified as the "cell-division cycle" proteins, 17 and they play a critical role during cytokinesis. 18 It has been reported that septins are indispensable in co-ordinating myosin motor proteins and bind with non-muscle myosin II to activate myosin II in interphase and dividing cells 19,20 and reorganizingx membrane during cytokinesis, 21 and anchoring the midbody ring structure in the membrane 22 when a daughter cell separates from its mother cell. Septins can assemble into hetero-oligomeric protein complexes which can further form filaments and microscopic bundles or ring structures in vitro and in vivo to control cellular processes.…”

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confidence: 99%

The role of septin 7 in physiology and pathological disease: A systematic review of current status

Wang

Fei

et al. 2018

J Cellular Molecular Medi

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Septins are a conserved family of cytoskeletal GTPases present in different organisms, including yeast, drosophila, Caenorhabditis elegans and humans. In humans, septins are involved in various cellular processes, including exocytosis, apoptosis, leukemogenesis, carcinogenesis and neurodegeneration. Septin 7 is unique out of 13 human septins. Mammalian septin 6, septin 7, septin 2 and septin 9 coisolate together in complexes to form the core unit for the generation of the septin filaments. Physiological septin filaments are hetero‐oligomeric complexes consisting of core septin hexamers and octamers. Furthermore, septin 7 plays a crucial role in cytokinesis and mitosis. Septin 7 is localized to the filopodia and branches of developing hippocampal neurons, and is the most abundant septin in the adult rat forebrain as well as a structural component of the human and mouse sperm annuli. Septin 7 is crucial to the spine morphogenesis and dendrite growth in neurons, and is also a structural constituent of the annulus in human and mouse sperm. It can suppress growth of some tumours such as glioma and papillary thyroid carcinoma. However, the molecular mechanisms of involvement of septin 7 in human disease, especially in the development of cancer, remain unclear. This review focuses on the structure, function and mechanism of septin 7 in vivo, and summarizes the role of septin 7 in cell proliferation, cytokinesis, nervous and reproductive systems, as well as the underlying molecular events linking septin 7 to various diseases, such as Alzheimer's disease, schizophrenia, neuropsychiatric systemic lupus erythematosus, tumour and so on.

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A septin requirement differentiates autonomous and contact-facilitated T cell proliferation

Cited by 23 publications

References 55 publications

In vivo imaging of the immune response upon systemic RNA cancer vaccination by FDG-PET

In vivo imaging of the immune response upon systemic RNA cancer vaccination by FDG-PET

Regulation of Store-Operated Ca2+ Entry by Septins

The role of septin 7 in physiology and pathological disease: A systematic review of current status

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