A Receptor/Cytoskeletal Movement Triggered by Costimulation During T Cell Activation

Wülfing, Christoph; Davis, Mark M.

doi:10.1126/science.282.5397.2266

Cited by 568 publications

(448 citation statements)

References 48 publications

(8 reference statements)

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“…The current data also identify a role for CD28 in T cell actin dynamics, a role previously suggested by data showing CD28 costimulation to be associated with Vav and SLP-76 signaling to the actin-regulatory Rac1 GTPase (35,39) and with cytoskeletally mediated lateral transport of antigen and various cell receptors (42). Recent data showing levels of WASp tyrosine phosphorylation (and, by extension, activation) to be higher in CD28-than in TCR-stimulated T cells (43), suggest that CD28 actin cytoskeletal effects may be realized via WASp.…”

Section: Discussionmentioning

confidence: 65%

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.

121

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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: 65%

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.

121

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“…In the resting lymphocyte, LFA-1 is held uniformly dispersed around the cell by interactions with the actin cytoskeleton. Inside-out signaling leads to release of LFA-1 from the cytoskeletal anchor, translocation to the IS, clustering and reallocation with the actin cytoskeleton [27][28][29][30].…”

Section: Discussionmentioning

confidence: 99%

“…Thirdly, chemokines induce LFA-1 clustering via phosphoinositide 3-OH kinase [26], an enzyme whose TCR-induced activation we have recently shown requires Vav1 [14]. Finally Vav1 may transduce TCR signals via Rho-family GTPases to the actin cytoskeleton and thus control release of LFA-1 from the cytoskeletal anchor, its actomyosin motor-directed movement to the IS [30] or its eventual reassociation with the cytoskeleton. Further work is needed to distinguish these possibilities.…”

Section: Discussionmentioning

confidence: 99%

Vav1 transduces TCR signals required for LFA‐1 function and cell polarization at the immunological synapse

et al. 2003

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Activation of T lineage cells through the TCR by peptide-MHC complexes on APC is critically dependent on rearrangement of the actin cytoskeleton. Vav1 is a guanine nucleotide exchange factor for members of the Rho/Rac family of GTPases which is activated following TCR stimulation, suggesting that it may transduce TCR signals to the activation of some or all actin-controlled processes. We show that Vav1-deficient double-positive thymocytes are less efficient at forming conjugates with APC presenting agonist peptide than wild-type cells are. Furthermore we demonstrate that Vav1 is required for TCR-induced activation of the integrin LFA-1, which is likely to explain the defect in conjugate formation. However, once Vav1-deficient cells form a conjugate, the assembly of proteins into an immunological synapse at the conjugate interface is normal. In contrast, thymocyte polarization is defective in the absence of Vav1, as judged by the relocalization of the microtubule-organizing center. These data demonstrate that Vav1 transduces signals to only a subset of cytoskeletondependent events at the immunological synapse.

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“…On physiological T-cell-APC interactions, CD28-B7 binding potentates synapse formation by increasing TCR-CD3 density through approximation of the interacting membranes. [29][30][31][32] Signal amplification through receptor clustering results in the integration of the TCR with costimulatory signalling that becomes obvious when compensating for a weak TCR signal. 33 Early events in T-cell activation are likely to require B7-CD28 engagement that helps to form the synapse, with the result that lowaffinity ligands can also successfully initiate T-cell signalling.…”

Section: Cd28 Cosignalling In Redirected T-cell Activation M Chmielewmentioning

confidence: 99%

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack

2010

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Adoptive immunotherapy of cancer using chimeric antigen receptor (CAR)-engineered T cells with redirected specificity showed efficacy in recent trials. In preclinical models, 'second-generation' CARs with CD28 costimulatory domain in addition to CD3z performed superior in redirecting T-cell effector functions and survival. Whereas CD28 costimulation sustains physiological T-cell receptor (TCR)-CD3 activation of naïve T cells, the impact of CD28 cosignalling on the threshold of CAR-mediated activation of pre-stimulated T cells without B7-CD28 recruitment remained unclear. Using CARs of different binding affinities, but same epitope specificity, we demonstrate that CD28 cosignalling neither lowered the antigen threshold nor the binding affinity for redirected T-cell activation. 'Affinity ceiling' above which increase in affinity does not increase T-cell activation was not altered. Accordingly, redirected tumor cell killing depended on the binding affinity but was likewise effective for CD3z and CD28-CD3z CARs. In contrast to CD3z, CD28-CD3z CAR-driven activation was not increased further by CD28-B7 engagement. However, CD28 cosignalling, which is required for interleukin-2 induction could not be replaced by high-affinity CD3z CAR binding or high-density antigen engagement. We conclude that CD28 CAR cosignalling does not alter the activation threshold but redirects T-cell effector functions.

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A Receptor/Cytoskeletal Movement Triggered by Costimulation During T Cell Activation

Cited by 568 publications

References 48 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

Vav1 transduces TCR signals required for LFA‐1 function and cell polarization at the immunological synapse

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack

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