T cell activation requires mitochondrial translocation to the immunological synapse

Quintana, Ariel; Schwindling, Christian; Wenning, Anna S.; Becherer, Ute; Rettig, Jens; Schwarz, Eva C.; Hoth, Markus

doi:10.1073/pnas.0703126104

Cited by 305 publications

(346 citation statements)

References 42 publications

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“…In agreement with previous studies (Quintana et al, 2007;Contento et al, 2010), Baixauli et al (2011) report that mitochondria accumulate at the IS following T-cell stimulation. They advance this model further and show that the fission factor DRP1 regulates mitochondria positioning close to the peripheral supramolecular activation cluster (pSMAC; Figure 1A), which together with the central SMAC form the IS in T cells.…”

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confidence: 93%

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Immune synapses: mitochondrial morphology matters

Junker

Hoth

2011

The EMBO Journal

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Proper positioning of mitochondria is critical for cellular function. Mitochondria localization close to synapses regulates signalling at neuronal and immune synapses (ISs). Vice versa, synapses influence activity, motility and the fusion/fission balance of close-by mitochondria. In this issue of The EMBO Journal, Baixauli et al (2011) identify a role for the mitochondrial fission factor dynamin-related protein 1 (DRP1) at the IS. DRP1 not only controls mitochondrial fission but also mitochondrial positioning to the IS, thereby modulating IS formation and downstream signalling.Main functions of mitochondria are energy supply, Ca 2 þ buffering, supply of metabolites and the sequestration of apoptotic factors (Hollenbeck and Saxton, 2005;Chan, 2006). It is not surprising that mitochondria thereby regulate a majority of cellular processes. In a simple model, (red) by fusion (yellow, mitofusions, OPA1) and fission (blue, DRP1) proteins lead to a partly interconnected, partly single organelle structure. After IS formation with an antigen-presenting cell, mitochondria are transported towards the IS, probably passively by centrosome movement and actively along tubulin and actin filaments. They accumulate with actin at the pSMAC, where they provide proper energy supply for synaptic signalling including centripetal flux of TCR microclusters towards the cSMAC by myosin motors. (B) Inhibition of DRP1 induces unopposed fusion of mitochondria, which appear as interconnected network, partly tethered to the ER by mitofusins, and they cannot be transported as well to the pSMAC.

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confidence: 93%

“…Mitochondria buffer Ca 2 þ at the IS thereby avoiding premature inactivation of the Ca 2 þ channels (Quintana et al, 2007). Baixauli et al (2011) report increased global Ca 2 þ signals following DRP1 impairment.…”

mentioning

confidence: 99%

Immune synapses: mitochondrial morphology matters

Junker

Hoth

2011

The EMBO Journal

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“…We also see this when using BM-DCs, suggesting that centriole positioning is likely to play a more significant role in the helper T cell versus CTLs, perhaps because of the centrality of synaptic secretion to their function. In Jurkat T cells, mitochondria translocated to the cytoplasm just inside the plasma membrane when stimulated with anti-CD3-coated beads (41), but in our system mitochondria are scattered throughout the activated T cell. This difference may reflect the earlier stage of T-cell development of the Jurkat cell relative to the more mature T-cell blasts used here.…”

Section: Discussionmentioning

confidence: 92%

CD4⁺T-cell synapses involve multiple distinct stages

Ueda

Morphew

McIntosh

et al. 2011

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

114

109

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One very striking feature of T-cell recognition is the formation of an immunological synapse between a T cell and a cell that it is recognizing. Formation of this complex structure correlates with cytotoxicity in the case of killer (largely CD8 + ) T-cell activity, or robust cytokine release and proliferation in the case of the much longer lived synapses formed by helper (CD4 + ) T cells. Here we have used electron microscopy and 3D tomography to characterize the synapses of antigen-specific CD4 + T cells recognizing B cells and dendritic cells at different time points. We show that there are at least four distinct stages in synapse formation, proceeding over several hours, including an initial stage involving invasive T-cell pseudopodia that penetrate deeply into the antigen-presenting cell, almost to the nuclear envelope. This must involve considerable force and may serve to widen the search for potential ligands on the surface of the cell being recognized. We also show that centrioles and the Golgi complex are always located immediately beneath the synapse and that centrioles are significantly shifted toward the late contact zone with either B lymphocytes or bone marrow-derived dendritic cells such as antigenpresenting cells, and that there are dynamic, stage-dependent changes in the organization of microtubules beneath the synapse. These data reinforce and extend previous data on cytotoxic T cells that one of the principal functions of the immunological synapse is to facilitate cytokine secretion into the synaptic cleft, as well as provide important insights into the overall dynamics of this phenomenon. microtubule organizing center | centrosome A prominent feature of many T-lymphocyte interactions with other cells on which it recognizes a particular antigen is the formation of an immunological synapse (IS). The formation of this structure correlates with robust signaling, lineage commitment, and fate determination of T cells (1-6) and the directed secretion of cytokines and/or cytotoxic molecules. There is a wholesale reorganization of the T cell's cytoskeleton, surface molecules, and organelles, and the loss of polarity regulators or guidance cues that negatively affect T-cell activation (7,8). Whereas a great deal has been learned about the dynamics of cell-surface and signaling molecules within this interface (9, 10), much less is known about changes within the cell, especially in the long-lived helper T cell, namely in antigen-presenting cell (APC) interactions, which can last for 6 or more h and need continuous T-cell receptor (TCR) engagement (11). Here electron microscopic studies are particularly valuable for their very high resolution, especially with the power of 3D tomography and highpressure freezing, which preserves cell structure more faithfully. Although a number of high-resolution electron microscopy studies of T cell-APC interactions have been reported (3,(12)(13)(14)(15), these involve studies of cytotoxic T or natural killer cells and their targets for only the first few minutes of CD4 + ...

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“…Alternatively, the caps may be sequestering channels to reduce Ca 2ϩ influx in areas outside of the IS. For example, if polarization of mitochondria, which import cytosolic Ca 2ϩ , produces a Ca 2ϩ gradient with low cytosolic Ca 2ϩ near the IS (Quintana et al, 2007), the CRAC channels in the cap would be in an area with the highest cytosolic Ca 2ϩ . This would inactivate the CRAC channels in caps, whereas cap formation removes channels from the areas near the IS, enhancing the Ca 2ϩ gradient.…”

Section: Discussionmentioning

confidence: 99%

“….1 cells on CD3, n ϭ 699; E6.1 cells on CD45, n ϭ 552; E6.1 cells on CD45 ϩ thapsigargin, n ϭ 487; E6.1 cells on CD45 ϩ thapsigargin ϩ ionomycin, n ϭ 550; 2-APB-treated E6.1 cells on CD3, n ϭ 489; EGTA-treated E6.1 cells on CD3, n ϭ 362; EGTAϩBAPTA-treated E6.1 cells on CD3, n ϭ 327; CCCP-treated E6.1 cells on CD3, n ϭ 445; PP2-treated E6.1 cells on CD3, n ϭ 356; JCaM1.6 cells on CD3, n ϭ 340; and Lck-reconstituted JCaM1.6 cells on CD3, n ϭ 259. and L). Some studies have reported a connection between mitochondrial activity and maintenance of CRAC currents (Quintana et al, 2006(Quintana et al, , 2007. We treated cells with CCCP to abolish mitochondrial potential, thus affecting both mitochondrial function and decreasing the magnitude of the CRAC current.…”

Section: Influx Of External Ca 2؉ Is Not Needed For Cap Formationmentioning

confidence: 99%

Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

Barr

Bernot

Srikanth

et al. 2008

MBoC

129

142

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The proteins STIM1 and Orai1 are the long sought components of the store-operated channels required in T-cell activation. However, little is known about the interaction of these proteins in T-cells after engagement of the T-cell receptor. We found that T-cell receptor engagement caused STIM1 and Orai1 to colocalize in puncta near the site of stimulation and accumulate in a dense structure on the opposite side of the T-cell. FRET measurements showed a close interaction between STIM1 and Orai1 both in the puncta and in the dense cap-like structure. The formation of cap-like structures did not entail rearrangement of the entire endoplasmic reticulum. Cap formation depended on TCR engagement and tyrosine phosphorylation, but not on channel activity or Ca 2؉ influx. These caps were very dynamic in T-cells activated by contact with superantigen pulsed B-cells and could move from the distal pole to an existing or a newly forming immunological synapse. One function of this cap may be to provide preassembled Ca 2؉ channel components to existing and newly forming immunological synapses. INTRODUCTIONT-cell activation in response to antigen induces and requires the elevation of intracellular Ca 2ϩ (Hogan et al., 2003;Quintana et al., 2005;Feske, 2007). T-cell receptor (TCR) engagement leads to activation of well-documented signal transduction pathways that cause a rapid release of Ca 2ϩ from the endoplasmic reticulum (ER; Samelson, 2002;Panyi et al., 2004;Gwack et al., 2007a). The depletion of Ca 2ϩ from this internal store then leads to the opening of ion channels in the plasma membrane (PM) allowing an influx of Ca 2ϩ from outside the cell. The store-operated channel responsible for Ca 2ϩ influx in T-cells is known as the Ca 2ϩ release-activated Ca 2ϩ (CRAC) channel, which has been studied by electrophysiological techniques for many years (Lewis, 2001;Prakriya and Lewis, 2003;Cahalan et al., 2007;Hewavitharana et al., 2007;Hogan and Rao, 2007;Putney, 2007a).Sustained elevation of cytosolic Ca 2ϩ is required for complete T-cell activation (Iezzi et al., 1998;Lewis, 2001;Hogan et al., 2003;Feske, 2007). High levels of intracellular Ca 2ϩ are necessary to maintain the interaction between a T-cell and antigen-presenting cell (APC) that leads to formation of the specialized contact surface known as the immunological synapse (IS). Increased Ca 2ϩ levels are also required for the activation of transcription factors. In particular, elevated Ca 2ϩ maintains prolonged nuclear accumulation of nuclear factor of activated T-cells (NFAT) by activating the phosphatase calcineurin that dephosphorylates NFAT, allowing it to translocate to the nucleus and activate genes such as IL2 (Hogan et al., 2003;Macian, 2005). Several hours of Ca 2ϩ influx are required to complete the T-cell activation program, which involves expression of a large number of activation-associated genes (Lewis, 2001;Macian et al., 2002;Hogan et al., 2003).Although sustained Ca 2ϩ influx in T-cells has been studied for decades, the proteins involved have only been ident...

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T cell activation requires mitochondrial translocation to the immunological synapse

Cited by 305 publications

References 42 publications

Immune synapses: mitochondrial morphology matters

Immune synapses: mitochondrial morphology matters

CD4⁺T-cell synapses involve multiple distinct stages

Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

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T cell activation requires mitochondrial translocation to the immunological synapse

Cited by 305 publications

References 42 publications

Immune synapses: mitochondrial morphology matters

Immune synapses: mitochondrial morphology matters

CD4+T-cell synapses involve multiple distinct stages

Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

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CD4⁺T-cell synapses involve multiple distinct stages