An Enigmatic Tail of CD28 Signaling

Boomer, Jonathan S.; Green, Jonathan M.

doi:10.1101/cshperspect.a002436

Cited by 207 publications

(208 citation statements)

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“…CD28 has a single cytoplasmic domain containing the YMMM and PYAP specific motifs, which upon phosphorylation by Src family kinases bind SH2 and SH3 containing proteins thereby initiating several signal transduction cascades (reviewed in ref. 45). CD81, a four transmembrane protein with short cytoplasmic N-and C-terminal domains lacks tyrosine activation motifs (46).…”

Section: Kinetics Of Early Signaling Events In T-cell Activation Depementioning

confidence: 99%

Complementary costimulation of human T-cell subpopulations by cluster of differentiation 28 (CD28) and CD81

Sagi¹,

Landrigan

Levy³

et al. 2012

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

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Cluster of differentiation 81 (CD81) is a widely expressed tetraspanin molecule that physically associates with CD4 and CD8 on the surface of human T cells. Coengagement of CD81 and CD3 results in the activation and proliferation of T cells. CD81 also costimulated mouse T cells that lack CD28, suggesting either a redundant or a different mechanism of action. Here we show that CD81 and CD28 have a preference for different subsets of T cells: Primary human naïve T cells are better costimulated by CD81, whereas the memory T-cell subsets and Tregs are better costimulated by CD28. The more efficient activation of naïve T cells by CD81 was due to prolonged signal transduction compared with that by CD28. We found that IL-6 played a role in the activation of the naïve T-cell subset by CD81. Combined costimulation through both CD28 and CD81 resulted in an additive effect on Tcell activation. Thus, these two costimulatory molecules complement each other both in the strength of signal transduction and in T-cell subset inclusions. Costimulation via CD81 might be useful for expansion of T cells for adoptive immunotherapy to allow the inclusion of naïve T cells with their broad repertoire.

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Section: Kinetics Of Early Signaling Events In T-cell Activation Depementioning

confidence: 99%

Complementary costimulation of human T-cell subpopulations by cluster of differentiation 28 (CD28) and CD81

Sagi¹,

Landrigan

Levy³

et al. 2012

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

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“…Both TCR and CD28 signals are required for a full T-cell response, resulting in, for example, production of the IL-2 cytokine. Although it lacks an intrinsic catalytic domain, the short 41 amino acid cytoplasmic tail of CD28 has highly conserved tyrosine-based motifs that are phosphorylated by cytoplasmic tyrosine kinases upon T-cell stimulation and that bind targets with SH2 domains in a pTyr-dependent manner, as well as proline-rich sequences that potentially bind SH3 domains (12). It therefore can help orchestrate the response to the signal from an APC, such as a B cell.…”

mentioning

confidence: 99%

Combinatorial proteomic analysis of intercellular signaling applied to the CD28 T-cell costimulatory receptor

Tian

Wang²,

Gish

et al. 2015

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

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Systematic characterization of intercellular signaling approximating the physiological conditions of stimulation that involve direct cell-cell contact is challenging. We describe a proteomic strategy to analyze physiological signaling mediated by the T-cell costimulatory receptor CD28. We identified signaling pathways activated by CD28 during direct cell-cell contact by global analysis of protein phosphorylation. To define immediate CD28 targets, we used phosphorylated forms of the CD28 cytoplasmic region to obtain the CD28 interactome. The interaction profiles of selected CD28-interacting proteins were further characterized in vivo for amplifying the CD28 interactome. The combination of the global phosphorylation and interactome analyses revealed broad regulation of CD28 and its interactome by phosphorylation. Among the cellular phosphoproteins influenced by CD28 signaling, CapZ-interacting protein (CapZIP), a regulator of the actin cytoskeleton, was implicated by functional studies. The combinatorial approach applied herein is widely applicable for characterizing signaling networks associated with membrane receptors with short cytoplasmic tails.uring some forms of intercellular communication, soluble growth factors are secreted by one cell type and bind specific transmembrane receptor tyrosine kinases (RTKs) present on neighboring cells. Activated RTKs then undergo autophosphorylation and also phosphorylate associated scaffold proteins, thereby creating docking sites for effector proteins with phosphotyrosine (pTyr)-recognition modules such as Src homology 2 (SH2) and pTyr-binding (PTB) domains (1). These immediate targets of growth-factor receptors control a variety of intracellular responses, typified by the activation of serine/ threonine protein kinases such as those involved in the ERK MAP kinase pathway. Growth-factor signaling therefore leads to extensive changes in both tyrosine and serine/threonine phosphorylation (2).The alterations in protein-protein interactions and posttranslational modifications elicited by transmembrane receptors can in principle be characterized by mass spectrometry (MS)-based proteomics (3-6). However, under circumstances that involve complex cell-cell interactions, identifying physiologically relevant signals using MS-based proteomics can be challenging. For example, obtaining a sufficiently robust response for MS analysis has often required the use of cells that overexpress a receptor of interest and are subjected to a nonphysiological stimulus. For this reason, experiments have often focused on specific, often stereotypic, aspects of the cellular response, rather than taking a more global approach. Moreover, cell-cell interactions are often typified by the interaction of multiple transmembrane receptor-ligand pairs, frequently involving membrane proteins that are not receptor kinases. Short-peptide motifs from such receptors that serve as potential ligands for downstream targets can be used as affinity probes for binding partners, but these experiments suffer from high fals...

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“…CD28 signaling enhances T cell survival, most likely through prevention of T cell apoptosis via inhibition of FasL (56) and stimulation of Bcl-x L expression (57). These antiapoptotic pathways are most likely mediated through the CD28 motifs YMNM and PYAPP and binding of p85 and GRB2, with a dependence on NF-kB activation (39).…”

Section: Discussionmentioning

confidence: 99%

“…4). The CD28 IC domain contains three main motifs that specifically associate with adaptor proteins and kinases, which, in turn, initiate different signaltransduction cascades (39). The proximal YMNM motif, when phosphorylated, binds p85 (a subunit of PI3K) and GRB2.…”

Section: Discussionmentioning

confidence: 99%

“…The CD28 and CD3ε IC domains are able to contribute to the reorganization of the cytoskeleton and formation of immune synapses. The CD28 IC domain, mainly through its PYAPP motif and activation of GRB2 and FILAMIN-A pathways, directs movement of CD28 to early immune synapses (39), whereas the CD3ε IC domain, mainly through recruitment of NCK, leads to activation of the RAS/RAF/ERK pathway and formation of immune synapses (51,52).…”

Section: Discussionmentioning

confidence: 99%

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TCRs Genetically Linked to CD28 and CD3ε Do Not Mispair with Endogenous TCR Chains and Mediate Enhanced T Cell Persistence and Anti-Melanoma Activity

Govers

Sebestyén

Roszik

et al. 2014

The Journal of Immunology

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Adoptive transfer of T cells that are gene engineered to express a defined TCR represents a feasible and promising therapy for patients with tumors. However, TCR gene therapy is hindered by the transient presence and effectiveness of transferred T cells, which are anticipated to be improved by adequate T cell costimulation. In this article, we report the identification and characterization of a novel two-chain TCR linked to CD28 and CD3ε (i.e., TCR:28ε). This modified TCR demonstrates enhanced binding of peptide–MHC and mediates enhanced T cell function following stimulation with peptide compared with wild-type TCR. Surface expression of TCR:28ε depends on the transmembrane domain of CD28, whereas T cell functions depend on the intracellular domains of both CD28 and CD3ε, with IL-2 production showing dependency on CD28:LCK binding. TCR:28ε, but not wild-type TCR, induces detectable immune synapses in primary human T cells, and such immune synapses show significantly enhanced accumulation of TCR transgenes and markers of early TCR signaling, such as phosphorylated LCK and ERK. Importantly, TCR:28ε does not show signs of off-target recognition, as evidenced by lack of TCR mispairing, as well as preserved specificity. Notably, when testing TCR:28ε in immune-competent mice, we observed a drastic increase in T cell survival, which was accompanied by regression of large melanomas with limited recurrence. Our data argue that TCR transgenes that contain CD28, and, thereby, may provide T cell costimulation in an immune-suppressive environment, represent candidate receptors to treat patients with tumors.

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An Enigmatic Tail of CD28 Signaling

Cited by 207 publications

References 210 publications

Complementary costimulation of human T-cell subpopulations by cluster of differentiation 28 (CD28) and CD81

Complementary costimulation of human T-cell subpopulations by cluster of differentiation 28 (CD28) and CD81

Combinatorial proteomic analysis of intercellular signaling applied to the CD28 T-cell costimulatory receptor

TCRs Genetically Linked to CD28 and CD3ε Do Not Mispair with Endogenous TCR Chains and Mediate Enhanced T Cell Persistence and Anti-Melanoma Activity

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