Lck Regulates the Threshold of Activation in Primary T Cells, While both Lck and Fyn Contribute to the Magnitude of the Extracellular Signal-Related Kinase Response

Lovatt, Matthew; Filby, Andrew; Parravicini, Valentino; Werlen, Guy; Palmer, Ed; Zamoyska, Rose

doi:10.1128/mcb.00168-06

Cited by 104 publications

(123 citation statements)

References 63 publications

(79 reference statements)

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“…The specific down-regulation of eIF6 in Lck −/− cells may result from a combination of multiple signaling defects. eIF6 has been shown to be up-regulated in mast cells by FceR1 crosslinking and to be inhibited by cyclosporin A (45), and Ca 2+ signaling is particularly compromised in the absence of Lck in both CD4 (15) and CD8 T cells (47). Additionally, eIF6 promoter activity has been shown to be regulated by GABP (48), an Etslike transcription factor partially regulated by ERK (49), which is less strongly activated in Lck −/− cells.…”

Section: Discussionmentioning

confidence: 99%

“…Of the two major SFK members in T cells, p56 Lck (Lck) and p59 Fyn (Fyn), Lck was shown to be the more influential for setting the threshold of T-cell triggering (14). In primary T cells in the absence of Lck, Fyn can substitute to some extent so that cells become activated, but through a more restricted set of signaling pathways (15). Removal of Lck is a useful means of manipulating TCR signal strength; therefore, we used Lck −/− mice expressing a tetracycline-inducible Lck transgene to abrogate Lck expression in peripheral T cells (16).…”

Section: Tcr Signaling Regulates Both Total Protein Synthesis and Spementioning

confidence: 99%

“…IL-2 is a key cytokine providing signals required for proliferation and survival of T cells during activation (27). Transcription of Il2 mRNA is regulated by activation-induced factors, such as NFAT (28) and AP1 (29), and, in weakly activated T cells, either in the absence of Lck (15) or with low affinity antigenic stimulation (Fig. 7A), production of IL-2 is impaired.…”

Section: Inefficient Ribosome Biogenesis In Lck −/− Cells Causes Loss Ofmentioning

confidence: 99%

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Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells

Tan

Knight

Sbarrato

et al. 2017

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

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Global transcriptomic and proteomic analyses of T cells have been rich sources of unbiased data for understanding T-cell activation. Lack of full concordance of these datasets has illustrated that important facets of T-cell activation are controlled at the level of translation. We undertook translatome analysis of CD8 T-cell activation, combining polysome profiling and microarray analysis. We revealed that altering T-cell receptor stimulation influenced recruitment of mRNAs to heavy polysomes and translation of subsets of genes. A major pathway that was compromised, when TCR signaling was suboptimal, was linked to ribosome biogenesis, a rate-limiting factor in both cell growth and proliferation. Defective TCR signaling affected transcription and processing of ribosomal RNA precursors, as well as the translation of specific ribosomal proteins and translation factors. Mechanistically, IL-2 production was compromised in weakly stimulated T cells, affecting the abundance of Myc protein, a known regulator of ribosome biogenesis. Consequently, weakly activated T cells showed impaired production of ribosomes and a failure to maintain proliferative capacity after stimulation. We demonstrate that primary T cells respond to various environmental cues by regulating ribosome biogenesis and mRNA translation at multiple levels to sustain proliferation and differentiation.

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Section: Discussionmentioning

confidence: 99%

Section: Tcr Signaling Regulates Both Total Protein Synthesis and Spementioning

confidence: 99%

Section: Inefficient Ribosome Biogenesis In Lck −/− Cells Causes Loss Ofmentioning

confidence: 99%

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Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells

Tan

Knight

Sbarrato

et al. 2017

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

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“…In contrast, in the WEDGE, it could reflect activation of an inhibitory feedback loop in response to a tonic TCR signal. Fyn, which is a less effective CD45 substrate and upregulated during thymic development and in peripheral T cells, could play a critical role in this process, potentially via its interactions with PAG/Cbp (29)(30)(31). Maturation-specific differences in signaling networks could also explain the hyperresponsiveness of DP and SP thymocytes and hyporesponsiveness of peripheral naïve CD4 ϩ T cells to the same stimuli (32,33).…”

Section: Discussionmentioning

confidence: 99%

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Hermiston¹,

Zikherman²,

Tan

et al. 2009

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

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The cooperative activity of protein tyrosine kinases and phosphatases plays a central role in regulation of T cell receptor (TCR) signal strength. Perturbing this balance, and thus the threshold for TCR signals, has profound impacts on T cell development and function. We previously generated mice containing a point mutation in the juxtamembrane wedge of the receptor-like protein tyrosine phosphatase CD45. Demonstrating the critical negative regulatory function of the wedge, the CD45 E613R (WEDGE) mutation led to a lymphoproliferative disorder (LPD) and a lupus-like autoimmune syndrome. Using genetic, cellular, and biochemical approaches, we now demonstrate that the CD45 wedge influences T cell development and function. Consistent with increased TCR signal strength, WEDGE mice have augmented positive selection and enhanced sensitivity to the CD4-mediated disease experimental autoimmune encephalitis (EAE). These correspond with hyperresponsive calcium and pERK responses to TCR stimulation in thymocytes, but surprisingly, not in peripheral T cells, where these responses are actually depressed. Together, the data support a role for the CD45 wedge in regulation of T cell responses in vivo and suggest that its effects depend on cellular context. autoimmunity ͉ tyrosine phosphatase ͉ tyrosine kinase ͉ thymocyte development T cell receptor (TCR) signal strength is influenced by the integration of multiple inputs including affinity for antigen, presence and activity of costimulatory molecules, and duration of the interaction with antigen-presenting cells (APCs) (1). Alterations in TCR signal strength impact many aspects of T cell biology including CD4 versus CD8 lineage commitment (1), effector and memory cell generation (2), and autoimmunity (3, 4). Currently, the factors defining signal strength and its functional outcome are incompletely understood.CD45, a receptor-like protein tyrosine phosphatase (RPTP) expressed on all nucleated hematopoietic cells, plays a critical positive regulatory role in antigen receptor signaling. Its absence in both mice and humans results in severe combined immunodeficiency (5, 6). CD45 mediates its effects, at least in part, by modulating the activation state of Src family protein tyrosine kinases (SFKs) (5, 7). Phosphorylation of the SFK C-terminal tyrosine by Csk inhibits the kinase while autophosphorylation of the catalytic domain tyrosine results in full activity. CD45 opposes Csk by dephosphorylating the negative regulatory tyrosine, generating a pool of primed SFKs capable of rapid activation upon receptor stimulation. In some cell types, CD45 can also dephosphorylate the catalytic tyrosine and negatively regulate SFKs.Regulation of CD45 itself is complex. Alternative splicing of the extracellular domain, regulated in a cell-and activation-specific manner, generates multiple isoforms differing in size and charge (5). Interestingly, CD45 polymorphisms influencing its alternative splicing, and thus isoform expression, are associated with several human autoimmune diseases (8). We initi...

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“…The T-cell activation threshold is a single-cell parameter and represents the minimum TCR signal required to elicit a response that triggers T-cell activation 3,9,41 Recent evidence suggests that the T-cell activation threshold can be modified by the following factors: (1) changes in TCR signal strength 39,42 ; (2) and Foxp1 expression in freshly isolated or in vitro-stimulated naive CD4 þ T cells. Purified naïve CD4 þ T cells were unstimulated (fresh) or stimulated using plate-bound anti-CD3 (1 mg ml À 1 ) and anti-CD28 (1 mg ml À 1 ) antibodies (Egr1 and Egr2, n ¼ 7; Klf2 and Foxp1, n ¼ 6; * Po0.05, **Po0.01 and ***Po0.001 by Student's t-test; NS, no significance).…”

Section: Discussionmentioning

confidence: 99%

The mediator subunit Med23 contributes to controlling T-cell activation and prevents autoimmunity

et al. 2014

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Lck Regulates the Threshold of Activation in Primary T Cells, While both Lck and Fyn Contribute to the Magnitude of the Extracellular Signal-Related Kinase Response

Cited by 104 publications

References 63 publications

Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells

Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

The mediator subunit Med23 contributes to controlling T-cell activation and prevents autoimmunity

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