Dynamin 2 regulates T cell activation by controlling actin polymerization at the immunological synapse

Gomez, Timothy S.; Hamann, Michael J.; McCarney, Sean; Savoy, Doris N.; Lubking, Casey M.; Heldebrant, Michael P.; Labno, Christine M.; McKean, David J.; McNiven, Mark A.; Burkhardt, Janis K.; Billadeau, Daniel D.

doi:10.1038/ni1168

Cited by 139 publications

(143 citation statements)

References 49 publications

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“…A connection of CD28 endocytosis with its cosignaling function is implied by data showing that the HIV accessory protein, Nef, enhances induction of both CD28 endocytosis and T cell activation (54,55). Similarly, linkages of endocytic pathway components with cell signaling/activation are suggested by the capacities of intersectins, dynamin, and other endocytic effectors to interact with signaling effectors like Src and Sos to promote MAP kinase pathway activation (51,56,57) and data showing that signaling protein-containing endosomes, for example, in sensory neurons, contribute to transduction of growth factor-activating signals (58). These data suggest that endosomes can serve as signaling platforms enabling the intersection of endocytic, actin regulatory, and signaling proteins.…”

Section: Discussionmentioning

confidence: 99%

“…These data are consistent with an essential role for the actin cytoskeleton in CD28 endocytosis and for the SNX9/p85 axis in creating an interface for the CD28-driven WASp activation required to link actin polymerization with CD28 internalization. Similarly, a putative role for dynamin in T cell actin remodeling may reflect SNX9-mediated coupling of dynamin to WASp (51). In addition to promoting CD28 endocytosis, SNX9 also appears critical to the coupling of CD28 engagement to NFAT activation.…”

Section: Discussionmentioning

confidence: 99%

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Interaction of the Wiskott–Aldrich syndrome protein with sorting nexin 9 is required for CD28 endocytosis and cosignaling in T cells

Badour

McGavin

Zhang

et al. 2007

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

119

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The Wiskott-Aldrich syndrome protein (WASp) plays a major role in coupling T cell antigen receptor (TCR) stimulation to induction of actin cytoskeletal changes required for T cell activation. Here, we report that WASp inducibly binds the sorting nexin 9 (SNX9) in T cells and that WASp, SNX9, p85, and CD28 colocalize within clathrin-containing endocytic vesicles after TCR/CD28 costimulation. SNX9, implicated in clathrin-mediated endocytosis, binds WASp via its SH3 domain and uses its PX domain to interact with the phosphoinositol 3-kinase regulatory subunit p85 and product, phosphoinositol (3,4,5)P 3. The data reveal ligationinduced CD28 endocytosis to be clathrin-and phosphoinositol 3-kinase-dependent and TCR/CD28-evoked CD28 internalization and NFAT activation to be markedly enhanced by SNX9 overexpression, but severely impaired by expression of an SNX9 mutant (SNX9⌬PX) lacking p85-binding capacity. CD28 endocytosis and CD28-evoked actin polymerization also are impaired in WASpdeficient T cells. These findings suggest that SNX9 couples WASp to p85 and CD28 so as to link CD28 engagement to its internalization and to WASp-mediated actin remodeling required for CD28 cosignaling. Thus, the WASp/SNX9/p85/CD28 complex enables a unique interface of endocytic, actin polymerizing, and signal transduction pathways required for CD28-mediated T cell costimulation.actin cytoskeleton ͉ costimulation ͉ lymphocyte activation ͉ signaling

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interaction of the Wiskott–Aldrich syndrome protein with sorting nexin 9 is required for CD28 endocytosis and cosignaling in T cells

Badour

McGavin

Zhang

et al. 2007

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

119

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“…Related to this notion, it has previously been suggested that dynamin 2 regulates T-cell activation through actin polymerization, but is not required for TCR internalization (25). This study mainly used overexpression and knockdown experiments in Jurkat cells and concluded that dynamin 2 was required for the up-regulation of the activation marker CD69 and for optimal ERK phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes

Willinger¹,

Staron²,

Ferguson³

et al. 2015

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

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Prolonged T-cell receptor (TCR) signaling is required for the proliferation of T lymphocytes. Ligation of the TCR activates signaling, but also causes internalization of the TCR from the cell surface. How TCR signaling is sustained for many hours despite lower surface expression is unknown. Using genetic inhibition of endocytosis, we show here that TCR internalization promotes continued TCR signaling and T-lymphocyte proliferation. T-cell–specific deletion of dynamin 2, an essential component of endocytosis, resulted in reduced TCR signaling strength, impaired homeostatic proliferation, and the inability to undergo clonal expansion in vivo. Blocking endocytosis resulted in a failure to maintain mammalian target of rapamycin (mTOR) activity and to stably induce the transcription factor myelocytomatosis oncogene (c-Myc), which led to metabolic stress and a defect in cell growth. Our results support the concept that the TCR can continue to signal after it is internalized from the cell surface, thereby enabling sustained signaling and cell proliferation.

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“…However, the C terminus of DLC1 that is included in tat DLC1 can also interact with other proteins (41), thus making other mechanisms of tat DLC1 action conceivable. Intriguing among the other interacting proteins is dynamin 2 (42), as it regulates actin accumulation at the T cell-APC interface (43). Changed actin dynamics are thus a prominent potential alternative for the mechanism of tat DLC1 function in the suppression of the dissolution of the T cell invaginations.…”

Section: Characterization Of the T Cell Invagination As Regulated Simmentioning

confidence: 99%

A Large T Cell Invagination with CD2 Enrichment Resets Receptor Engagement in the Immunological Synapse

Singleton

Parvaze

Dama

et al. 2006

The Journal of Immunology

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T cell activation is driven by the TCR and complemented by costimulation. We have studied the dynamics of ligand-engagement of the costimulatory receptor CD2 in T cell/APC couples. Thousands of ligand-engaged CD2 molecules were included in a large T cell invagination at the center of the cellular interface within 1 min of cell couple formation. The structure and regulation of this invagination shared numerous features with phagocytosis and macropinocytosis. Three observations further characterize the invagination and the inclusion of CD2: 1) numerous ligand-engaged receptors were enriched in and internalized through the T cell invagination, none as prominently as CD2; 2) dissolution of the T cell invagination and CD2 engagement were required for effective proximal T cell signaling; and 3) the T cell invagination was uniquely sensitive to the affinity of the TCR for peptide-MHC. Based on this characterization, we speculate that the T cell invagination, aided by CD2 enrichment, internalizes parts of the TCR signaling machinery to reset T cell signaling upon agonist-mediated, stable APC contact.

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Dynamin 2 regulates T cell activation by controlling actin polymerization at the immunological synapse

Cited by 139 publications

References 49 publications

Interaction of the Wiskott–Aldrich syndrome protein with sorting nexin 9 is required for CD28 endocytosis and cosignaling in T cells

Interaction of the Wiskott–Aldrich syndrome protein with sorting nexin 9 is required for CD28 endocytosis and cosignaling in T cells

Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes

A Large T Cell Invagination with CD2 Enrichment Resets Receptor Engagement in the Immunological Synapse

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