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1.
J Exp Med ; 219(6)2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35587822

RESUMO

Evidence is emerging that immune responses not only play a part in the central nervous system (CNS) in diseases but may also be relevant for healthy conditions. We discovered a major role for the interleukin-4 (IL-4)/IL-4 receptor alpha (IL-4Rα) signaling pathway in synaptic processes, as indicated by transcriptome analysis in IL-4Rα-deficient mice and human neurons with/without IL-4 treatment. Moreover, IL-4Rα is expressed presynaptically, and locally available IL-4 regulates synaptic transmission. We found reduced synaptic vesicle pools, altered postsynaptic currents, and a higher excitatory drive in cortical networks of IL-4Rα-deficient neurons. Acute effects of IL-4 treatment on postsynaptic currents in wild-type neurons were mediated via PKCγ signaling release and led to increased inhibitory activity supporting the findings in IL-4Rα-deficient neurons. In fact, the deficiency of IL-4Rα resulted in increased network activity in vivo, accompanied by altered exploration and anxiety-related learning behavior; general learning and memory was unchanged. In conclusion, neuronal IL-4Rα and its presynaptic prevalence appear relevant for maintaining homeostasis of CNS synaptic function.


Assuntos
Interleucina-4 , Receptores de Interleucina-4 , Animais , Interleucina-4/metabolismo , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Receptores de Interleucina-4/metabolismo , Transdução de Sinais
2.
Elife ; 112022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-35050850

RESUMO

T cell activation requires engagement of a cognate antigen by the T cell receptor (TCR) and the co-stimulatory signal of CD28. Both TCR and CD28 aggregate into clusters at the plasma membrane of activated T cells. While the role of TCR clustering in T cell activation has been extensively investigated, little is known about how CD28 clustering contributes to CD28 signalling. Here, we report that upon CD28 triggering, the BAR-domain protein sorting nexin 9 (SNX9) is recruited to CD28 clusters at the immunological synapse. Using three-dimensional correlative light and electron microscopy, we show that SNX9 generates membrane tubulation out of CD28 clusters. Our data further reveal that CD28 clusters are in fact dynamic structures and that SNX9 regulates their stability as well as CD28 phosphorylation and the resulting production of the cytokine IL-2. In summary, our work suggests a model in which SNX9-mediated tubulation generates a membrane environment that promotes CD28 triggering and downstream signalling events.


Assuntos
Antígenos CD28 , Membrana Celular , Transdução de Sinais/genética , Nexinas de Classificação , Animais , Antígenos CD28/genética , Antígenos CD28/metabolismo , Membrana Celular/química , Membrana Celular/metabolismo , Humanos , Sinapses Imunológicas/genética , Sinapses Imunológicas/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Células Jurkat , Ativação Linfocitária/genética , Camundongos , Camundongos Transgênicos , Fosforilação , Receptores de Antígenos de Linfócitos T/metabolismo , Nexinas de Classificação/genética , Nexinas de Classificação/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo
3.
Mol Biol Cell ; 32(9): 892-902, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33534630

RESUMO

Endocytic trafficking controls the density of molecules at the plasma membrane and by doing so, the cell surface profile, which in turn determines how cells interact with their environment. A full apprehension of any cellular process necessitates understanding how proteins associated with the plasma membrane are endocytosed, how they are sorted after internalization, and if and how they are recycled to the plasma membrane. To date, it is still difficult to experimentally gain access to this information, even more to do it in a quantitative way. Here we present a toolset based on photoactivation of fluorescent proteins that enabled us to generate quantitative information on endocytosis, incorporation into sorting and recycling endosomes, delivery from endosomes to the plasma membrane, and on the type of vesicles performing intracellular transport. We illustrate these approaches by revealing striking differences in the endocytic trafficking of T-cell receptor and CD4, which bind to the same molecule at the surface of antigen-presenting cells during T-cell activation.


Assuntos
Imunofluorescência/métodos , Transporte Proteico/fisiologia , Vesículas Transportadoras/fisiologia , Transporte Biológico , Membrana Celular/fisiologia , Endocitose/fisiologia , Endossomos/metabolismo , Humanos , Células Jurkat , Proteínas/metabolismo , Vesículas Transportadoras/metabolismo
4.
Cells ; 8(11)2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31690048

RESUMO

: T cell activation is immediately followed by internalization of the T cell receptor (TCR). TCR endocytosis is required for T cell activation, but the mechanisms supporting removal of TCR from the cell surface remain incompletely understood. Here we report that TCR endocytosis is linked to the clathrin-independent carrier (CLIC) and GPI-enriched endocytic compartments (GEEC) endocytic pathway. We show that unlike the canonical clathrin cargo transferrin or the adaptor protein Lat, internalized TCR accumulates in tubules shaped by the small GTPase Cdc42 and the Bin/amphiphysin/Rvs (BAR) domain containing protein GRAF1 in T cells. Preventing GRAF1-positive tubules to mature into endocytic vesicles by expressing a constitutively active Cdc42 impairs the endocytosis of TCR, while having no consequence on the uptake of transferrin. Together, our data reveal a link between TCR internalization and the CLIC/GEEC endocytic route supported by Cdc42 and GRAF1.


Assuntos
Endocitose/fisiologia , Proteínas Ativadoras de GTPase/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Clatrina/metabolismo , Humanos , Células Jurkat
5.
Nat Commun ; 10(1): 4392, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31558725

RESUMO

The targeted endocytic recycling of the T cell receptor (TCR) to the immunological synapse is essential for T cell activation. Despite this, the mechanisms that underlie the sorting of internalised receptors into recycling endosomes remain poorly understood. To build a comprehensive picture of TCR recycling during T cell activation, we developed a suite of new imaging and quantification tools centred on photoactivation of fluorescent proteins. We show that the membrane-organising proteins, flotillin-1 and -2, are required for TCR to reach Rab5-positive endosomes immediately after endocytosis and for transfer from Rab5- to Rab11a-positive compartments. We further observe that after sorting into in Rab11a-positive vesicles, TCR recycles to the plasma membrane independent of flotillin expression. Our data suggest a mechanism whereby flotillins delineate a fast Rab5-Rab11a endocytic recycling axis and functionally contribute to regulate the spatial organisation of these endosomes.


Assuntos
Membrana Celular/metabolismo , Endocitose , Endossomos/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab5 de Ligação ao GTP/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Células Jurkat , Proteínas de Membrana , Microscopia Confocal , Transporte Proteico , Receptores de Antígenos de Linfócitos T/genética
6.
Nat Commun ; 9(1): 1597, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29686427

RESUMO

Endocytosis of surface receptors and their polarized recycling back to the plasma membrane are central to many cellular processes, such as cell migration, cytokinesis, basolateral polarity of epithelial cells and T cell activation. Little is known about the mechanisms that control the organization of recycling endosomes and how they connect to receptor endocytosis. Here, we follow the endocytic journey of the T cell receptor (TCR), from internalization at the plasma membrane to recycling back to the immunological synapse. We show that TCR triggering leads to its rapid uptake through a clathrin-independent pathway. Immediately after internalization, TCR is incorporated into a mobile and long-lived endocytic network demarked by the membrane-organizing proteins flotillins. Although flotillins are not required for TCR internalization, they are necessary for its recycling to the immunological synapse. We further show that flotillins are essential for T cell activation, supporting TCR nanoscale organization and signaling.


Assuntos
Endocitose/fisiologia , Ativação Linfocitária/fisiologia , Proteínas de Membrana/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Humanos , Sinapses Imunológicas/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Transdução de Sinais/imunologia
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