Lck-independent Triggering of T-cell Antigen Receptor Signal Transduction by Staphylococcal Enterotoxins

Yamasaki, Satoshi; Tachibana, Makoto; Shinohara, Nobukata; Iwashima, Makio

doi:10.1074/jbc.272.23.14787

Cited by 31 publications

(30 citation statements)

References 44 publications

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“…The observation of NFAT activation and IL-2 production in response to SEE by Lck-deficient T cells has been interpreted as a reflection of Lck dispensability (19). However, our observation that PP2 enhances the response of some primary T cell subsets to SEE argues that not only is Lck dispensable in this response, but it may play a negative regulatory role.…”

Section: Resultscontrasting

confidence: 51%

“…This result conclusively demonstrates that it is the kinase activity of Lck that plays a negative regulatory role on SAg-induced T cell activation. It also implies that the inhibition of IL-2 production by PP2 in T cells that do not express Lck is due to inhibition of Fyn, which then is essential for activation of these cells (19).…”

Section: Resultsmentioning

confidence: 99%

“…Although Lck is activated after TCR engagement with SAg (31), it is not required for SEE-induced T cell activation, as illustrated by the ability of the Lck-deficient T cell line JCaM1.6 to respond to SEE (19). To analyze the contribution of Lck to the response to SEE, we examined the effect of blocking the activity of this kinase in PBMC using the pharmacological inhibitor PP2, a compound that selectively inhibits the tyrosine kinases Lck and Fyn (32).…”

Section: Resultsmentioning

confidence: 99%

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Superantigen Stimulation Reveals the Contribution of Lck to Negative Regulation of T Cell Activation

Criado

Madrenas

2004

The Journal of Immunology

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The conventional paradigm of T cell activation through the TCR states that Lck plays a critical activating role in this signaling process. However, the T cell response to bacterial superantigens does not require Lck. In this study we report that not only is Lck dispensable for T cell activation by superantigens, but it actively inhibits this signaling pathway. Disruption of Lck function, either by repression of Lck gene expression or by selective pharmacologic inhibitors of Lck, led to increased IL-2 production in response to superantigen stimulation. This negative regulatory effect of Lck on superantigen-induced T cell responses required the kinase activity of Lck and correlated with early TCR signaling, but was independent of immunological synapse formation and TCR internalization. Our data demonstrate that the multistage role of Lck in T cell signaling includes the activation of a negative regulatory pathway of T cell activation.

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Section: Resultscontrasting

confidence: 51%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Superantigen Stimulation Reveals the Contribution of Lck to Negative Regulation of T Cell Activation

Criado

Madrenas

2004

The Journal of Immunology

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“…This might be due to the unique features of superantigen binding to the TCR in this system, which neither requires nor involves CD4 (47). In support of this possibility, triggering of TCR signaling with staphylococcal enterotoxins has been shown to be unaffected in Lck defective T cells (48). Furthermore, T cells from Fyn Ϫ/Ϫ mice showed reduced responses to SEB (44).…”

Section: Discussionmentioning

confidence: 62%

Defective Signaling to Fyn by a T Cell Antigen Receptor Lacking the α-Chain Connecting Peptide Motif

Ulivieri

Peter

Orsini

et al. 2001

Journal of Biological Chemistry

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A key role in the communication between the ␣␤TCR and the CD3/ complex is played by a specific motif within the connecting peptide domain of the TCR ␣ chain (␣-CPM). T cell hybridomas expressing an ␣-CPM-mutated TCR show a dramatic impairment in antigen-driven interleukin-2 production. This defect can be complemented by a calcium ionophore, indicating that activation of the calcium pathway is impaired. Several lines of evidence implicate Fyn in the regulation of calcium mobilization, at least in part through the activation of phospholipase C␥. Here we have investigated the potential involvement of Fyn in the TCR ␣-CPM signaling defect. Using T cell hybridomas expressing either a wild-type TCR or an ␣-CPM mutant, we show that Fyn fails to be activated by the mutant receptor following SEB binding and fails to generate tyrosine-phosphorylated Pyk2, a member of the focal adhesion kinase family. This defect correlated with an impairment in phospholipase C␥ phosphorylation. Production of interlukin-2 and activation of the transcription factor NF-AT in response to triggering of the TCR ␣-CPM mutant with SEB were fully restored in the presence of constitutively active Fyn. Hence the signaling defect generated by the TCR ␣-CPM mutation results at least in part from an impaired coupling of the TCR⅐CD3 complex to Fyn activation.

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“…Superantigen-MHC complexes induce TCR triggering, but, in contrast to pMHC, do not require the SFK Lck (27,28). To define a potential critical role of Lck in DC-mediated TCR triggering amplification, we compared the TCR-activating potency of superantigen-loaded DCs and nonprofessional APCs.…”

Section: Dcs Do Not Amplify Tcr Triggering In Lck-independent Ag Presmentioning

confidence: 99%

Dendritic Cells Sensitize TCRs through Self-MHC-Mediated Src Family Kinase Activation

Meraner

Hořejšı́

Wölpl

et al. 2007

The Journal of Immunology

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It is unclear whether peptide-MHC class II (pMHC) complexes on distinct types of APCs differ in their capacity to trigger TCRs. In this study, we show that individual cognate pMHC complexes displayed by dendritic cells (DCs), as compared with nonprofessional APCs, are far better in productively triggering Ag-specific TCRs independently of conventional costimulation. As we further show, this is accomplished by the unique ability of DCs to robustly activate the Src family kinases (SFKs) Lck and Fyn in T cells even in the absence of cognate peptide. Instead, this form of SFK activation depends on interactions of DC-displayed MHC with TCRs of appropriate restriction, suggesting a central role of self-pMHC recognition. DC-mediated SFK activation leads to “TCR licensing,” a process that dramatically increases sensitivity and magnitude of the TCR response to cognate pMHC. Thus, TCR licensing, besides costimulation, is a main mechanism of DCs to present Ag effectively.

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Lck-independent Triggering of T-cell Antigen Receptor Signal Transduction by Staphylococcal Enterotoxins

Abstract: Superantigens (SAgs) activate T-cells in a manner

Cited by 31 publications

References 44 publications

Superantigen Stimulation Reveals the Contribution of Lck to Negative Regulation of T Cell Activation

Superantigen Stimulation Reveals the Contribution of Lck to Negative Regulation of T Cell Activation

Defective Signaling to Fyn by a T Cell Antigen Receptor Lacking the α-Chain Connecting Peptide Motif

Dendritic Cells Sensitize TCRs through Self-MHC-Mediated Src Family Kinase Activation

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