Initiation of T cell signaling by CD45 segregation at 'close contacts'

Chang, Veronica T.; Fernandes, Ricardo A.; Ganzinger, Kristina A.; Lee, Steven F.; Siebold, Christian; McColl, James; Jönsson, Peter; Palayret, Matthieu; Harlos, K.; Coles, C.H.; Jones, E Y; Lui, Yuan; Huang, Elizabeth; Gilbert, Robert J.C.; Klenerman, David; Aricescu, A. Radu; Davis, Simon J.

doi:10.1038/ni.3392

Cited by 261 publications

(401 citation statements)

References 64 publications

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“…Therefore, we hypothesize NK signal integration occurs by the relative sizedependent colocalization of receptors at the NK IS, and this is the explanation for the functional differences observed for elongated ligands. Considering the differences observed at a nanometer-scale, our results further support recent evidence that immune cell receptors show a nanometer-scale organization, with functional associated implications [19,22,50,[52][53][54][55]. Interestingly, there is mounting evidence that the molecular mechanisms behind immune inhibition are in part spatially restricted and common to various immune cells such as T, B and NK cells [56][57][58][59].…”

supporting

confidence: 86%

“…The molecular dimensions of CD45 and CD148 have also been reported to affect T cell functionality [18]. More recently, the initiation of T cell signaling was confirmed by the CD45 segregation at close contact points [19]. In NK cells, elongation of activating and inhibitory NK cell receptor ligands has been shown to affect NK cell activation and inhibition, respectively [14,15].…”

Section: Nk Cell Signal Integration | Fret Nanoscale Localization | Nmentioning

confidence: 97%

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Nanoscale colocalization of NK cell activating and inhibitory receptors controls signal integration

Tomaz

Pereira

Guerra

et al. 2018

Preprint

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NK cell responses depend on the balance of signals from inhibitory and activating receptors. However, how the integration of antagonistic signals occurs upon NK cell-target cell interaction is not fully understood. Here, we provide evidence that NK cell inhibition via the inhibitory receptor Ly49A is dependent on its relative colocalization at nanometer-scale with the activating receptor NKG2D upon immune synapse (IS) formation. NKG2D and Ly49A signal integration and colocalization was studied using NKG2D-GFP and Ly49A-RFP-expressing primary NK cells, forming ISs with NIH3T3 target cells, with or without expression of single chain trimer (SCT) H2-D d and an extended form of SCT H2-D d -CD4 MHC-I molecules. Nanoscale colocalization was assessed by Förster resonance energy transfer (FRET) between NKG2D-GFP and Ly49A-RFP and measured for each synapse. In the presence of their respective cognate ligands, NKG2D and Ly49A colocalize at a nanometer scale leading to NK cell inhibition. However, increasing the size of the Ly49A ligand reduced the nanoscale colocalization with NKG2D consequently impairing Ly49A-mediated inhibition. Thus, our data shows NK cell signal integration is critically dependent on the dimensions of NK cell ligand-receptor pairs by affecting their relative nanometer-scale colocalization at the IS. Together, our results suggest the balance of NK cell signals, and NK cell responses, are determined by the relative nanoscale colocalization of activating and inhibitory receptors in the immune synapse. NK cell signal integration | FRET nanoscale localization | NKG2D | Ly49ACorrespondence:david.tomaz@kcl.ac.uk, r.henriques@ucl.ac.uk, k.gould@imperial.ac.uk Introduction NK cell activation is dependent on a different array of germline-encoded receptors capable of triggering effector responses against infection [1][2][3] and cellular transformation [4,5], and yet maintaining tolerance towards healthy cells and tissues [6,7]. NK cell functionality is widely characterized by a balance between activating and inhibitory receptors [8,9]. However, upon immune synapse formation, how NK cells integrate signals from functionally antagonistic receptors, is not yet fully understood [10]. One major hypothesis to explain immune signal integration is based on the kinetic segregation (K-S) model [11]. This model states that the balance of antagonistic signals is mediated by the equilibrium of phosphorylation (kinases) and dephosphorylation (phosphatases), which depends on the relative colocalization of receptors and their associated signaling molecules upon synapse formation. This hypothesis has been validated using T cells, in the context of TCR triggering [12,13] and, more recently, NK cells [14,15]. The K-S model suggests immune inhibition, upon immune synapse formation, is maintained by the dephosphorylation of tyrosines in stimulatory receptors (e.g ITAMs-associated receptors such as TCR-CD3 or NKG2D-DAP12), due to a nanoscale colocalization with receptors bearing phosphatase activity (e.g. CD45, CD148) or with t...

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supporting

confidence: 86%

Section: Nk Cell Signal Integration | Fret Nanoscale Localization | Nmentioning

confidence: 97%

Nanoscale colocalization of NK cell activating and inhibitory receptors controls signal integration

Tomaz

Pereira

Guerra

et al. 2018

Preprint

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“…The transmembrane tyrosine phosphatase CD45 protein is an essential regulator of T and B cell antigen receptor signaling in the immunological synapse by negatively and positively tuning the activity of either Lck in T cells or Lyn, Fyn, and Lck in B cells (5)(6)(7). Several isoforms of the CD45 protein are generated by alternative splicing of exons 4-6 encoding extracellular domains A, B, and C, or O in the absence of the 3 exons (i.e., CD45RA, CD45RB, CD45RC, and CD45RO) and conferring differences in size and charge (8,9).…”

Section: Introductionmentioning

confidence: 99%

Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells

Picarda¹,

Bézie²,

Boucault³

et al. 2017

JCI Insight

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“…For T cells, it was shown that the exclusion of CD45 and enrichment of the SFK Lck upon target cell binding induce phosphotyrosinylation of the T cell receptor and, thereby, initiate signaling (31). It is thought that this initial phosphorylation step is a result of local clustering of receptor and tyrosine kinases as well as an exclusion of tyrosine phosphatases (32).…”

Section: Discussionmentioning

confidence: 99%

The Activating C-type Lectin-like Receptor NKp65 Signals through a Hemi-immunoreceptor Tyrosine-based Activation Motif (hemITAM) and Spleen Tyrosine Kinase (Syk)

Bauer

Wotapek

Zöller

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillNKp65 is an activating human C-type lectin-like receptor (CTLR) triggering cellular cytotoxicity and cytokine secretion upon high-affinity interaction with the cognate CTLR keratinocyte-associated C-type lectin (KACL) selectively expressed by human keratinocytes. Previously, we demonstrated that NKp65-mediated cellular cytotoxicity depends on tyrosine 7, located in a cytoplasmic sequence motif of NKp65 resembling a hemi-immunoreceptor tyrosine-based activation motif (hemITAM). HemITAMs have been reported for a few activating myeloid-specific CTLRs, including Dectin-1 and CLEC-2, and consist of a single tyrosine signaling unit preceded by a triacidic motif. Upon receptor engagement, the hemITAM undergoes phosphotyrosinylation and specifically recruits spleen tyrosine kinase (Syk), initiating cellular activation. In this study, we addressed the functionality of the putative hemITAM of NKp65. We show that NKp65 forms homodimers and is phosphorylated at the hemITAM-embedded tyrosine 7 upon engagement by antibodies or KACL homodimers. HemITAM phosphotyrosinylation initiates a signaling pathway involving and depending on Syk, leading to cellular activation and natural killer (NK) cell degranulation. However, although NKp65 utilizes Syk for NK cell activation, a physical association of Syk with the NKp65 hemITAM could not be detected, unlike shown previously for the hemITAM of myeloid CTLR. Failure of NKp65 to recruit Syk is not due to an alteration of the triacidic motif, which rather affects the efficiency of hemITAM phosphotyrosinylation. In summary, NKp65 utilizes a hemITAM-like motif for cellular activation that requires Syk, although Syk appears not to be recruited to NKp65.

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Initiation of T cell signaling by CD45 segregation at 'close contacts'

Cited by 261 publications

References 64 publications

Nanoscale colocalization of NK cell activating and inhibitory receptors controls signal integration

Nanoscale colocalization of NK cell activating and inhibitory receptors controls signal integration

Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells

The Activating C-type Lectin-like Receptor NKp65 Signals through a Hemi-immunoreceptor Tyrosine-based Activation Motif (hemITAM) and Spleen Tyrosine Kinase (Syk)

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