A LAT Mutation That Inhibits T Cell Development Yet Induces Lymphoproliferation

Sommers, Connie L.; Park, Cheung-Seog; Lee, Jan; Feng, Chiguang; Fuller, Claudette L.; Grinberg, Alexander; Hildebrand, Jay A.; Lacaná, Emanuela; Menon, Rashmi K.; Shores, Elizabeth W.; Samelson, Lawrence E.; Love, Paul E.

doi:10.1126/science.1069066

Cited by 266 publications

(385 citation statements)

References 20 publications

(1 reference statement)

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“…Importantly, the pathology developed in these two mouse models encompasses hypergammaglobulinemia E and G1, massive lymphocytic infiltration of the lungs, and tissue eosinophilia and is thus reminiscent of allergic inflammation. Crosslinking of the TCR-CD3 complexes expressed at the surface of CD4 ϩ T cells from LatY136F mice fails to induce detectable PLC-␥1 activation and Ca 2ϩ mobilization (5). A similar signaling defect also exists in the ␥␦ T cells that expand in Lat3YF mice (6).…”

mentioning

confidence: 88%

“…The mutation of LAT tyrosine 136 in LatY136F mice inhibits PLC-␥1 binding and activation (4,5), which is illustrated in Fig. 2A where cross-linking of the TCR present on the surface of CD4 ϩ T cells isolated from LatY136F mice failed to stimulate Ca 2ϩ influx.…”

Section: Ca 2ϩ Mobilization Through Cyslt 1 In Activated Cd4 ϩ T Cellmentioning

confidence: 99%

“…A knockin mutation, called LatY136F, where tyrosine 136 of LAT was replaced by a phenylalanine, caused a fatal lymphoproliferative disorder involving polyclonal CD4 ϩ T cells that chronically produced type 2 cytokines such as IL-4, IL-5, and IL-13 (4,5). A compound knockin mutation, called Lat3YF, where tyrosines 175, 195 and 235 were replaced by phenylalanine, resulted in the selective development and expansion of ␥␦ T cells, which spontaneously deployed a Th2-like effector program (6).…”

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confidence: 99%

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The Type 1 Cysteinyl Leukotriene Receptor Triggers Calcium Influx and Chemotaxis in Mouse αβ- and γδ Effector T Cells

Prinz

Grégoire

Mollenkopf

et al. 2005

The Journal of Immunology

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Linker for activation of T cells (LAT) is essential for T cell activation. Mice with mutations of distinct LAT tyrosine residues (LatY136F and Lat3YF) develop lymphoproliferative disorders involving TCR αβ or γδ T cells that trigger symptoms resembling allergic inflammation. We analyzed whether these T cells share a pattern of gene expression that may account for their pathogenic properties. Both LatY136F αβ and Lat3YF γδ T cells expressed high levels of the type 1 cysteinyl leukotriene receptor (CysLT1). Upon binding to the 5(S)-hydroxy-6(R)-S-cysteinylglycyl-7,9-trans-11,14-cis-eicosatetraenoic acid (LTD4) cysteinyl leukotriene, CysLT1 induced Ca2+ flux and caused chemotaxis in both LatY136F αβ and Lat3YF γδ T cells. Wild-type in vitro-activated T cells, but not resting T cells, also migrated toward LTD4 however with a lower magnitude than T cells freshly isolated from LatY136F and Lat3YF mice. These results suggest that CysLT1 is likely involved in the recruitment of activated αβ and γδ T cells to inflamed tissues.

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confidence: 88%

Section: Ca 2ϩ Mobilization Through Cyslt 1 In Activated Cd4 ϩ T Cellmentioning

confidence: 99%

mentioning

confidence: 99%

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The Type 1 Cysteinyl Leukotriene Receptor Triggers Calcium Influx and Chemotaxis in Mouse αβ- and γδ Effector T Cells

Prinz

Grégoire

Mollenkopf

et al. 2005

The Journal of Immunology

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“…It has been shown both in vitro (16) and in vivo (17,18) that tyrosine phosphorylation of LAT at position 136 in the mouse (132 in human, which is the numbering system used in Materials and Methods and Figs. 3 and 8, because the Abs were made against the human phosphopeptides) is critical for the activation of PLC␥1.…”

Section: Phosphorylation Of the Adapter Protein Lat Is Impaired In Thmentioning

confidence: 99%

Adaptive Tolerance and Clonal Anergy Are Distinct Biochemical States

Chiodetti

Choi

Barber

et al. 2006

The Journal of Immunology

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Adaptive tolerance is a process by which T cells become desensitized when Ag stimulation persists following an initial immune response in vivo. To examine the biochemical changes in TCR signaling present in this state, we used a mouse model in which Rag2−/− TCR-transgenic CD4+ T cells were transferred into CD3ε−/− recipients expressing their cognate Ag. Compared with naive T cells, adaptively tolerant T cells had normal levels of TCR and slightly increased levels of CD4. Following activation with anti-TCR and anti-CD4 mAbs, the predominant signaling block in the tolerant cells was at the level of Zap70 kinase activity, which was decreased 75% in vitro. Phosphorylations of the Zap70 substrates (linker of activated T cells and phospholipase Cγ1 were also profoundly diminished. This proximal defect impacted mostly on the calcium/NFAT and NF-κB pathways, with only a modest decrease in ERK1/2 phosphorylation. This state was contrasted with T cell clonal anergy in which the RAS/MAPK pathway was preferentially impaired and there was much less inhibition of Zap70 kinase activity. Both hyporesponsive states manifested a block in IκB degradation. These results demonstrate that T cell adaptive tolerance and clonal anergy are distinct biochemical states, possibly providing T cells with two molecular mechanisms to curtail responsiveness in different biological circumstances.

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“…As a consequence of this exaggerated TH2 polarization, serum IgG1 concentrations were 5000-fold higher than in wild-type mice, serum IgE concentrations were in the range of several mg/ml, instead of a few µg/ml, and peripheral tissues were massively infiltrated with eosinophils. The differentiation of TCRγδ T cells was unaffected Sommers et al, 2002). Likewise, knock-in mice bearing point mutations of the adapter-binding three distal tyrosines of LAT (Y175F, Y195F and Y235F) displayed a complete block in the differentiation of TCRαβ T cells and an abnormal differentiation of TCRγδ T cells, also resulting in an exaggerated TH2 polarization and massive proliferation.…”

Section: Latmentioning

confidence: 99%

Negative Signaling in Fc Receptor Complexes

Daëron

Lesourne

2006

Advances in Immunology

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Cell activation results from the transient displacement of an active balance between positive and negative signaling. This displacement depends in part on the engagement of cell surface receptors by extracellular ligands. Among these are Receptors for the Fc portion of immunoglobulins (FcRs). FcRs are widely expressed by cells of hematopoietic orign. When binding antibodies, FcRs provide these cells with immunoreceptors capable of triggering numerous biological responses in response to specific antigen. FcR-dependent cell activation is regulated by negative signals which are generated together with positive signals within signalosomes that form upon FcR engagement. Many molecules involved in positive signaling, including the FcRβ subunit, the src kinase lyn, the cytosolic adapter Grb2, the transmembrane adapters LAT and NTAL, are indeed also involved in negative signaling. A major player in negative regulation of FcR signaling is the inositol 5-phosphatase SHIP1. Several layers of negative regulation operate sequentially as FcRs are engaged by extracellular ligands of increasing valency. A background protein tyrosine phosphatasedependent negative regulation maintains cells in a « resting » state. SHIP1-dependent negative regulation can be detected as soon as high-affinity FcRs are occupied by antibodies in the absence of antigen. It increases when activating FcRs are engaged by multivalent ligands and, further when FcR aggregation increases, accounting for the bell-shaped dose-response curve observed in excess of ligand. Finally, F-actin skeleton-associated high-molecular weight SHIP1, recruited to phopshorylated ITIMs, concentrates in signaling complexes when activating FcRs are coengaged with inhibitory FcRs by immune complexes. Based on these data, activating and inhibitory FcRs could be used for new therapeutic approaches of immune disorders.

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A LAT Mutation That Inhibits T Cell Development Yet Induces Lymphoproliferation

Cited by 266 publications

References 20 publications

The Type 1 Cysteinyl Leukotriene Receptor Triggers Calcium Influx and Chemotaxis in Mouse αβ- and γδ Effector T Cells

The Type 1 Cysteinyl Leukotriene Receptor Triggers Calcium Influx and Chemotaxis in Mouse αβ- and γδ Effector T Cells

Adaptive Tolerance and Clonal Anergy Are Distinct Biochemical States

Negative Signaling in Fc Receptor Complexes

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