MTOC translocation modulates IS formation and controls sustained T cell signaling

Martín-Cófreces, Noa B.; Robles‐Valero, Javier; Cabrero, José Román; Mittelbrunn, Marı́a; Gordon-Alonso, Mónica; Sung, Ching-Hwa; Alarcón, Balbino; Vázquez, Jesús; Sánchez-Madrid, Francisco

doi:10.1083/jcb.200801014

Cited by 163 publications

(216 citation statements)

References 58 publications

(82 reference statements)

Supporting

Mentioning

203

Contrasting

Unclassified

Order By: Relevance

“…As recently shown by Martín-Cófreces et al (36), although disruption of MTOC translocation inhibited T-cell Golgi polarization and IL-2 secretion, it only partially blocked CD69 upregulation (Fig. S7).…”

Section: Antagonist Pmhc-induced T-cell Polarization Fails To Recruitsupporting

confidence: 80%

T-cell antagonism by short half-life pMHC ligands can be mediated by an efficient trapping of T-cell polarization toward the APC

Carreño

Riquelme

González

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

T-cell activation results from productive T-cell receptor (TCR) engagement by a cognate peptide-MHC (pMHC) complex on the antigen presenting cell (APC) surface, a process leading to the polarization of the T-cell secretory machinery toward the APC interface. We have previously shown that the half-life of the TCR/ pMHC interaction and the density of pMHC on the APC are two parameters determining T-cell activation. However, whether the half-life of the TCR/pMHC interaction can modulate the efficiency of T-cell secretory machinery polarization toward an APC still remains unclear. Here, by using altered peptide ligands conferring different half-lives to the TCR/pMHC interaction, we have tested how this parameter can control T-cell polarization. We observed that only TCR/pMHC interactions with intermediate half-lives can promote the assembly of synapses that lead to T-cell activation. Strikingly, intermediate half-life interactions can be competed out by short half-life interactions, which can efficiently promote T-cell polarization and antagonize T-cell activation that was induced by activating intermediate half-life interactions. However, short TCR/ pMHC interactions fail at promoting phosphorylation of signaling molecules at the T-cell-APC contact interface, which are needed for T-cell activation. Our data suggest that although intermediate half-life pMHC ligands promote assembly of activating synapses, this process can be inhibited by short half-life antagonistic pMHC ligands, which promote the assembly of non activating synapses.immunological synapse | T-cell receptor | T-cell receptor half-life | dendritic cells

show abstract

Section: Antagonist Pmhc-induced T-cell Polarization Fails To Recruitsupporting

confidence: 80%

T-cell antagonism by short half-life pMHC ligands can be mediated by an efficient trapping of T-cell polarization toward the APC

Carreño

Riquelme

González

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

Section: The Centrosome Marks the Waymentioning

confidence: 99%

“…Additionally in CD8+ CTLs, suboptimal activation of the TCR can allow centrosomal-independent exocytosis of lytic granules before centrosome translocation [23,24]. Nonetheless, full activation of T lymphocytes largely depends on centrosome polarization [17].…”

Section: The Centrosome Marks the Waymentioning

confidence: 99%

“…Centrosome or microtubule-organizing centre (MTOC; Glossary) localization determines this initial polarity during development, establishing the site of Golgi localization and the trafficking of vesicles and mitochondria [16]. These events are paralleled in T cells as early analysis of T cell activation established the direct involvement of the centrosome in the localization of the Golgi apparatus (GA) at the IS (Figure 1) [5,7,8,[17][18][19].Early upon TCR activation, the centrosome localizes to the IS and rapidly polymerizes α/β tubulin dimers in microtubules [18], which organize a profuse network of microtubules at the T cell-APC contact area [18,20]. This dynamic network, regulated by microtubuleassociated proteins (MAPs) and tubulin post-translational modifications (PTMs; Box 1), provides a platform for intracellular transport and integration of the actin and tubulin cytoskeletons [19].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Immune synapse: conductor of orchestrated organelle movement

Martín-Cófreces¹,

Baixauli²,

Sánchez-Madrid³

2014

Trends in Cell Biology

View full text Add to dashboard Cite

SummaryTo ensure proper cell function, intracellular organelles are not randomly distributed within the cell, but polarized and highly constrained by the cytoskeleton and associated adaptor proteins. This relationship between distribution and function was originally found in neurons and epithelial cells; however, recent evidence suggests that it is a more general phenomenon that occurs in many highly specialized cells including the immune T cells. Recent studies reveal that the orchestrated redistribution of organelles is dependent on antigen specific activation and immune-synapse formation of T cells. This review highlights the functional implications of organelle polarization in early T cell activation and examines recent findings on how the immune synapse sets the rhythm of organelle motion and the spread of the activation signal to the nucleus. KeywordsImmune synapse; microcluster; signalosome; mitochondria; vesicle; microtubule Overview of the immune synapseT cell activation starts with an initial wave of signalling that depends on the activation of surface receptors, but subsequent propagation of the signal appears to depend on intracellular compartments, in a sequence driven by the actin and tubulin cytoskeletons [1]. The study of neural synapses highlighted the importance of cell polarity and the specific localization of organelles and clusters of receptors at the pre-and post-synaptic terminals. Despite its transient nature, recent evidence shows that the immune synapse (IS) shares these same neuronal features.The IS is the interface between a T lymphocyte and an antigen presenting cell (APC). During the formation and stabilization of the IS, membrane microdomains and the cytoskeleton reorganize and promote the segregation of membrane and intracellular signaling proteins within the T cell, such as the T cell receptor (TCR), integrins, tyrosine Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts kinases and scaffold proteins such as Linker for activation of T cells (LAT) (Figure 1 and Glossary). The TCR and associated molecules (TCR signalosomes) form microclusters that move to congregate in the central area (central supramolecular activation cluster; cSMAC) of the IS, whereas adhesion receptors such as integrins reorganize in a surrounding external ring called the peripheral or pSMAC ( Figure 2) [2]. In addition, phosphorylation and dephosphorylation, protein-protein interactions and degradation of important molecules such as the TCR-accompanying CD3 complex, tyrosine kinases, phosphatases and adaptor molecules also control receptor activation [3,4]. The polarization of several organelles occurs during T cell stimulation with important roles, such as the centrosome, Golgi apparatus, mitochondria, endoplasmic reticulum and the multivesicular bodies (MVB) [5][6][7][8][9][10]. These rearrangements at the IS promote the activation of signaling pathways that propagate to the nucleus. Signals activating nuclear transcription factors in combination with polarity proteins, such as partit...

show abstract

“…22 The ability of Rab29 to interact with the minus-end motor dynein, which is responsible for TCR trafficking to the polarized centrosome during IS assembly, 23 was assessed in co-immunoprecipitation assays. Rab29 was found to constitutively interact with dynein in Jurkat cells (Figure 5f).…”

mentioning

confidence: 99%

The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis

et al. 2015

View full text Add to dashboard Cite

Accumulating evidence underscores the T-cell immune synapse (IS) as a site of intense vesicular trafficking, on which productive signaling and cell activation crucially depend. Although the T-cell antigen receptor (TCR) is known to exploit recycling to accumulate to the IS, the specific pathway that controls this process remains to be elucidated. Here we demonstrate that the small GTPase Rab29 is centrally implicated in TCR trafficking and IS assembly. Rab29 colocalized and interacted with Rab8, Rab11 and IFT20, a component of the intraflagellar transport system that regulates ciliogenesis and participates in TCR recycling in the non-ciliated T cell, as assessed by co-immunoprecipitation and immunofluorescence analysis. Rab29 depletion resulted in the inability of TCRs to undergo recycling to the IS, thereby compromizing IS assembly. Under these conditions, recycling TCRs accumulated in Rab11 + endosomes that failed to polarize to the IS due to defective Rab29-dependent recruitment of the dynein microtubule motor. Remarkably, Rab29 participates in a similar pathway in ciliated cells to promote primary cilium growth and ciliary localization of Smoothened. These results provide a function for Rab29 as a regulator of receptor recycling and identify this GTPase as a shared participant in IS and primary cilium assembly. T-cell activation is triggered by T-cell antigen receptor (TCR) engagement by MHC-bound peptide dispayed by an antigen presenting cell (APC). While a substantial proportion of the TCR has long been known to be associated with recycling endosomes, 1 it is only recently that the central function of this pool has emerged with the finding that, on assembly of the specialized interface with the APC, known as the immune synapse (IS), intracellular TCRs are delivered to this location by polarized recycling. 2 This process ensures a steady supply of TCRs at the IS to sustain signaling for T-cell activation 3 and has been co-opted by other receptors, such as the transferrin receptor (TfR) and the chemokine receptor CXCR4, 4,5 as well as membrane-bound signaling mediators, such as the kinase Lck and the adaptor LAT. 6,7 Receptor recycling is orchestrated by the small GTPases Rab4 and Rab11. 8 Cargo specificity is achieved with the assistance of specific regulators and effectors. The TCR recycling pathway has only started to be delineated with the identification of specific mediators, which include Rab35 and its GAP EPI64C 9 and the actin adaptor WASH 10 . Specific combinations of Rabs and SNAREs have been recently associated with recycling endosomes carrying either Lck, or TCRζ and LAT. 11 We have moreover identified IFT20 12 and other components of the intraflagellar transport (IFT) system, which regulates ciliary assembly and function, 13 as unexpected regulators of TCR recycling in the non-ciliated T cell. 14 Recently a Rab GTPase subfamily, which includes Rab29, Rab32 and Rab38, has been implicated in trafficking of the Salmonella-containing vacuole (SCV) in infected epithelial cells. 15,16 Rab32 and Rab38 ...

show abstract

MTOC translocation modulates IS formation and controls sustained T cell signaling

Cited by 163 publications

References 58 publications

T-cell antagonism by short half-life pMHC ligands can be mediated by an efficient trapping of T-cell polarization toward the APC

T-cell antagonism by short half-life pMHC ligands can be mediated by an efficient trapping of T-cell polarization toward the APC

Immune synapse: conductor of orchestrated organelle movement

The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis

Contact Info

Product

Resources

About