A role for the immunological synapse in lineage commitment of CD4 lymphocytes

Maldonado, Roberto; Irvine, Darrell J.; Schreiber, Robert D.; Glimcher, Laurie H.

doi:10.1038/nature02916

Cited by 168 publications

(157 citation statements)

References 30 publications

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“…What this might be is suggested by the fact that these invasive pseudopodia would significantly increase the surface area of T cell-APC contact, at least fivefold over a "flat" interaction, thus enabling the T cell to sample much more of the possible antigens on the APC surface. T cells are very sensitive to their peptide-MHC ligands, able to detect even one molecule (32,33), and although this is sufficient for the cell to stop, more peptide-MHC agonist ligands are usually needed (3)(4)(5)(6)(7)(8)(9)(10) to make a full response (2). Interestingly, this remarkable probing activity has not been seen in fluorescence studies of T cell-APC interactions, perhaps because of a lack of resolution and/or its rapidity.…”

Section: Discussionmentioning

confidence: 99%

“…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)(2)(3)(4)(5)(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).…”

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confidence: 99%

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CD4⁺T-cell synapses involve multiple distinct stages

Ueda

Morphew

McIntosh

et al. 2011

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

113

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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

CD4⁺T-cell synapses involve multiple distinct stages

Ueda

Morphew

McIntosh

et al. 2011

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

113

109

View full text Add to dashboard Cite

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“…During the early stage of T-cell differentiation, the cells potentially integrate different environment clues and ultimately allow cells to move towards committing to a particular T-cell lineage 29,30 . The fate decision involves the competition of various transcription factors that dictate different T-cell differentiation programs [31][32][33] .…”

Section: Discussionmentioning

confidence: 99%

MiR-125a targets effector programs to stabilize Treg-mediated immune homeostasis

et al. 2015

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Although different autoimmune diseases show discrete clinical features, there are common molecular pathways intimately involved. Here we show that miR-125a is downregulated in peripheral CD4 þ T cells of human autoimmune diseases including systemic lupus erythematosus and Crohn's disease, and relevant autoimmune mouse models. miR-125a stabilizes both the commitment and immunoregulatory capacity of Treg cells. In miR-125a-deficient mice, the balance appears to shift from immune suppression to inflammation, and results in more severe pathogenesis of colitis and experimental autoimmune encephalomyelitis (EAE). The genome-wide target analysis reveals that miR-125a suppresses several effector T-cell factors including Stat3, Ifng and Il13. Using a chemically synthesized miR-125a analogue, we show potential to re-programme the immune homeostasis in EAE models. These findings point to miR-125a as a critical factor that controls autoimmune diseases by stabilizing Treg-mediated immune homeostasis.

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“…Differences in downstream signalling events following IL-4R ligation result in differential Th cell lineage commitment. 24 Polymorphisms in the IL-4Ra sequence are sufficient to alter Th2 disease phenotypes. 25 However, the BALB/c variant of IL-4Ra exhibits amino-acid substitutions, which result in less avid ligand binding and more rapid ligand dissociation, compared to the B6 variant.…”

Section: Discussionmentioning

confidence: 99%