Fyn Regulates the Duration of TCR Engagement Needed for Commitment to Effector Function

Filby, Andrew; Seddon, Benedict; Kleczkowska, Joanna; Salmond, Robert J.; Tomlinson, Peter; Šmída, Michal; Lindquist, Jonathan A.; Schraven, Burkhart; Zamoyska, Rose

doi:10.4049/jimmunol.179.7.4635

Cited by 67 publications

(90 citation statements)

References 71 publications

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“…Conversely, sustained Lck activation can result in a loss of tolerance and the onset of disease (3,74). We propose that elevated TCR-induced SFK activation in TCPTP-deficient T cells may be responsible for the inflammatory and autoimmune phenotype in Lck-Cre;Ptpn2 fl/fl mice.…”

Section: Discussionmentioning

confidence: 99%

T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice

Wiede

Shields²,

Chew³

et al. 2011

J. Clin. Invest.

192

269

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Many autoimmune diseases exhibit familial aggregation, indicating that they have genetic determinants. Single nucleotide polymorphisms in PTPN2, which encodes T cell protein tyrosine phosphatase (TCPTP), have been linked with the development of several autoimmune diseases, including type 1 diabetes and Crohn's disease. In this study, we have identified TCPTP as a key negative regulator of TCR signaling, which might explain the association of PTPN2 SNPs with autoimmune disease. We found that TCPTP dephosphorylates and inactivates Src family kinases to regulate T cell responses. Using T cell-specific TCPTP-deficient mice, we established that TCPTP attenuates T cell activation and proliferation in vitro and blunts antigen-induced responses in vivo. TCPTP deficiency lowered the in vivo threshold for TCR-dependent CD8 + T cell proliferation. Consistent with this, T cell-specific TCPTP-deficient mice developed widespread inflammation and autoimmunity that was transferable to wild-type recipient mice by CD8 + T cells alone. This autoimmunity was associated with increased serum levels of proinflammatory cytokines and anti-nuclear antibodies, T cell infiltrates in non-lymphoid tissues, and liver disease. These data indicate that TCPTP is a critical negative regulator of TCR signaling that sets the threshold for TCR-induced naive T cell responses to prevent autoimmune and inflammatory disorders arising.

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Section: Discussionmentioning

confidence: 99%

T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice

Wiede

Shields²,

Chew³

et al. 2011

J. Clin. Invest.

192

269

View full text Add to dashboard Cite

show abstract

“…However, recent evidence suggested that this kinase also generates negative signals that downregulate T cell and MC activation. For example, treatment of BMMCs with the specific Fyn inhibitor SU6656 or small interfering RNAmediated knockdown of Fyn leads to increased phosphorylation of AMPK, its upstream kinase LKB1, and its downstream target acetyl-CoA carboxylase in the absence of FcεRI stimulation (59), and Fyn negatively regulates TCR signaling in CD8 T cells (60). Our data add to the notion that Fyn kinase acts as a negative modulator of specific immune responses, limiting, in our particular case, the amount of TLR4-triggered TNF.…”

Section: Discussionmentioning

confidence: 99%

Protein Tyrosine Kinase Fyn Regulates TLR4-Elicited Responses on Mast Cells Controlling the Function of a PP2A-PKCα/β Signaling Node Leading to TNF Secretion

Martín-Ávila

Medina-Tamayo

Ibarra-Sánchez

et al. 2016

The Journal of Immunology

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Mast cells produce proinflammatory cytokines in response to TLR4 ligands, but the signaling pathways involved are not fully described. In this study, the participation of the Src family kinase Fyn in the production of TNF after stimulation with LPS was evaluated using bone marrow–derived mast cells from wild-type and Fyn-deficient mice. Fyn−/− cells showed higher LPS-induced secretion of preformed and de novo–synthesized TNF. In both cell types, TNF colocalized with vesicle-associated membrane protein (VAMP)3-positive compartments. Addition of LPS provoked coalescence of VAMP3 and its interaction with synaptosomal-associated protein 23; those events were increased in the absence of Fyn. Higher TNF mRNA levels were also observed in Fyn-deficient cells as a result of increased transcription and greater mRNA stability after LPS treatment. Fyn−/− cells also showed higher LPS-induced activation of TAK-1 and ERK1/2, whereas IκB kinase and IκB were phosphorylated, even in basal conditions. Increased responsiveness in Fyn−/− cells was associated with a lower activity of protein phosphatase 2A (PP2A) and augmented activity of protein kinase C (PKC)α/β, which was dissociated from PP2A and increased its association with the adapter protein neuroblast differentiation–associated protein (AHNAK, desmoyokin). LPS-induced PKCα/β activity was associated with VAMP3 coalescence in WT and Fyn-deficient cells. Reconstitution of MC-deficient Wsh mice with Fyn−/− MCs produced greater LPS-dependent production of TNF in the peritoneal cavity. Our data show that Fyn kinase is activated after TLR4 triggering and exerts an important negative control on LPS-dependent TNF production in MCs controlling the inactivation of PP2Ac and activation of PKCα/β necessary for the secretion of TNF by VAMP3+ carriers.

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“…2). However, Fyn is also involved in feedback inhibition of TCR signaling through phosphorylation of the transmembrane adapter phosphoprotein associated with glycosphingolipid-enriched domains that recruits Csk and results in phosphorylation and inhibition of Lck function (45). Feedback inhibition of TCR signaling by Fyn is implicated in the induction of T cell anergy (46,47), and it is possible that MAPK-dependent inhibition of rpS6 Ser 240/4 phosphorylation also has important functional consequences.…”

Section: Discussionmentioning

confidence: 99%

MAPK, Phosphatidylinositol 3-Kinase, and Mammalian Target of Rapamycin Pathways Converge at the Level of Ribosomal Protein S6 Phosphorylation to Control Metabolic Signaling in CD8 T Cells

Salmond

Emery

Okkenhaug

et al. 2009

The Journal of Immunology

Self Cite

110

106

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Ribosomal protein S6 (rpS6) is a key component of the translational machinery in eukaryotic cells and is essential for ribosome biogenesis. rpS6 is phosphorylated on evolutionarily conserved serine residues, and data indicate that rpS6 phosphorylation might regulate cell growth and protein synthesis. Studies in cell lines have shown an important role for the serine kinase mammalian target of rapamycin (mTOR) in rpS6 phosphorylation, further linking rpS6 to control of cellular metabolism. rpS6 is essential in T cells because its deletion in mouse double-positive thymocyte cells results in a complete block in T cell development; however, the signaling pathway leading to rpS6 phosphorylation downstream of TCR stimulation has yet to be fully characterized. We show that maximal TCR-induced rpS6 phosphorylation in CD8 T cells requires both Lck and Fyn activity and downstream activation of PI3K, mTOR, and MEK/ERK MAPK pathways. We demonstrate that there is cross-talk between the PI3K and MAPK pathways as well as PI3K-independent mTOR activity, which result in differential phosphorylation of specific rpS6 serine residues. These results place rpS6 phosphorylation as a point of convergence for multiple crucial signaling pathways downstream of TCR triggering.

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Fyn Regulates the Duration of TCR Engagement Needed for Commitment to Effector Function

Cited by 67 publications

References 71 publications

T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice

T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice

Protein Tyrosine Kinase Fyn Regulates TLR4-Elicited Responses on Mast Cells Controlling the Function of a PP2A-PKCα/β Signaling Node Leading to TNF Secretion

MAPK, Phosphatidylinositol 3-Kinase, and Mammalian Target of Rapamycin Pathways Converge at the Level of Ribosomal Protein S6 Phosphorylation to Control Metabolic Signaling in CD8 T Cells

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