High-Affinity Ligands Can Trigger T Cell Receptor Signaling Without CD45 Segregation

Al-Aghbar, Mohammad Ameen; Chu, Yu‐Xia; Chen, Bing Mae; Roffler, Steve R.

doi:10.3389/fimmu.2018.00713

Cited by 19 publications

(18 citation statements)

References 87 publications

(113 reference statements)

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“…Because CD45 is excluded it has been proposed that the segregation of CD45 itself may be sufficient to initiate TCR signaling (26). However, studies using tethered antibodies that bind to the TCR with high affinity indicate that exclusion of CD45 is not a strict requirement (64). Additional studies have reported that the T cell:APC synapse also functions as a site of sustained signaling and receptor downregulation upon strong stimulation (65,66).…”

Section: Discussionmentioning

confidence: 99%

CD45 functions as a signaling gatekeeper in T cells

Courtney

Shvets

et al. 2019

Sci. Signal.

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T cells require the protein tyrosine phosphatase CD45 to detect and respond to antigen because it activates the Src family kinase Lck, which phosphorylates the T cell antigen receptor (TCR) complex. CD45 activates Lck by opposing the negative regulatory kinase Csk. Paradoxically, CD45 has also been implicated in suppressing TCR signaling by dephosphorylating the same signaling motifs within the TCR complex upon which Lck acts. We sought to reconcile these observations using chemical and genetic perturbations of the Csk/CD45 regulatory axis incorporated with computational analyses. Specifically, we titrated the activities of Csk and CD45 and assessed their influence on Lck activation, TCR-associated ζ-chain phosphorylation, and more downstream signaling events. Acute inhibition of Csk revealed that CD45 suppressed ζ-chain phosphorylation and was necessary for a regulatable pool of active Lck, thereby interconnecting the activating and suppressive roles of CD45 that tune antigen discrimination. CD45 suppressed signaling events that were antigen independent or induced by low-affinity antigen but not those initiated by high-affinity antigen. Together, our findings reveal that CD45 acts as a signaling “gatekeeper,” enabling graded signaling outputs while filtering weak or spurious signaling events.

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Section: Discussionmentioning

confidence: 99%

CD45 functions as a signaling gatekeeper in T cells

Courtney

Shvets

et al. 2019

Sci. Signal.

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“…Due to its abundance and its large extracellular domain, CD45 has been used by many authors over years as a tool molecule, which can be used to efficiently immobilize T cells without affecting their biology 61 , although some reports indicate that CD45 segregation may nevertheless impact T cell activation 62 , depending on the isotype of the antibody used 63 . Recent reports show that CD45 segregation is not required to stimulate Jurkat T cells by immobilized recombinant monovalent antibodies raised against CD3 64 . We tested other antibodies, such as aCD43 or aMHCI following ref.…”

Section: Resultsmentioning

confidence: 99%

Controlling T cells shape, mechanics and activation by micropatterning

Sadoun¹,

Biarnes-Pelicot

Ghesquiere-Dierickx

et al. 2020

Preprint

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We designed a strategy, based on a careful examination of the activation capabilities of proteins and antibodies used as substrates for adhering T cells, coupled to protein microstamping. This allowed us to control at the same time the position, shape, mechanics and activation state of T cells. Once adhered on shaped patterns we examined the capacities of T cells to be activated with soluble aCD3, in comparison to T cells adhered to a continuously decorated substrate with the same density of ligands. We show that, in our hand, adhering onto an anti CD45 (aCD45) antibody decorated surface is not affecting T cell calcium fluxes, even adhered on variable size micro-patterns. We further demonstrate this by expressing MEGF10 as a non immune adhesion receptor in T cells to obtain the very same spreading area on PLL substrates and Young modulus than immobilized cells on aCD45, while retaining similar activation capabilities using soluble aCD3 or through model APC contacts. We propose that our system is a way to test activation or anergy of T cells with defined adhesion and mechanical characteristics, and may allow to dissect fine details of these mechanisms since it allows to observe homogenised populations in standardized T cell activation assays.

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“…Another important observation at a larger-length scale was that the exclusion of phosphatase CD45 from the TCR was also different between the ligations of the TCR with an agonist or antagonist. The exclusion of CD45 occurred only when the TCR binds to an agonist [ 13 , 78 , 81 , 82 ]. The exclusion of CD45 determines the signaling outcome by modulating the degree of ITAM phosphorylation, and thus, this can be a critical mechanism to discriminate agonist against antagonist.…”

Section: Mechanical Regulation Of T Cell Activationmentioning

confidence: 99%

Regulations of T Cell Activation by Membrane and Cytoskeleton

Kaizuka

2020

Membranes

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Among various types of membrane proteins that are regulated by cytoskeleton, the T cell receptor (TCR) greatly benefits from these cellular machineries for its function. The T cell is activated by the ligation of TCR to its target agonist peptide. However, the binding affinity of the two is not very strong, while the T cell needs to discriminate agonist from many nonagonist peptides. Moreover, the strength and duration of the activation signaling need to be tuned for immunological functions. Many years of investigations revealed that dynamic acto-myosin cytoskeletons and plasma membranes in T cells facilitate such regulations by modulating the spatiotemporal distributions of proteins in plasma membranes and by applying mechanical loads on proteins. In these processes, protein dynamics in multiple scales are involved, ranging from collective molecular motions and macroscopic molecular organizations at the cell–cell interface to microscopic changes in distances between receptor and ligand molecules. In this review, details of how cytoskeletons and membranes regulate these processes are discussed, with the emphasis on how all these processes are coordinated to occur within a single cell system.

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High-Affinity Ligands Can Trigger T Cell Receptor Signaling Without CD45 Segregation

Cited by 19 publications

References 87 publications

CD45 functions as a signaling gatekeeper in T cells

CD45 functions as a signaling gatekeeper in T cells

Controlling T cells shape, mechanics and activation by micropatterning

Regulations of T Cell Activation by Membrane and Cytoskeleton

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