Induction of T Helper Type 2 Immunity by a Point Mutation in the LAT Adaptor

Aguado, Enrique; Richelme, Sylvie; Nuñez-Cruz, Selene; Miazek, Arkadiusz; Mura, Anne-Marie; Richelme, Mireille; Guo, Xiaojun; Sainty, Danielle; He, Hai‐Tao; Malissen, Bernard; Malissen, Marie

doi:10.1126/science.1069057

Cited by 254 publications

(378 citation statements)

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“…For specific inhibition, the cells were preincubated for 3 min with dilutions of MK571 ranging from 10 Ϫ5 to 10 Ϫ8 M, and the same concentration of MK571 was added to the corresponding lower chambers. In all experiments, all media contained equal concentrations of 0.1% ethanol and 0.1% DMSO to exclude artifacts resulting from the organic solvent of LTD 4 and MK571, respectively. After incubation for 2 h at 37°C, the upper chamber was removed, and the cells in the lower chamber resuspended and transferred to tubes.…”

Section: Chemotaxis Assaymentioning

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).…”

mentioning

confidence: 99%

“…Among them, the adaptor molecule linker for activation of T cells (LAT) 4 plays a crucial role in that it coordinates the assembly of signaling complexes through multiple tyrosine residues within its intracytoplasmic segment. Most of the signaling activity of LAT appears funneled through the four C-terminal tyrosine residues found at positions 136, 175, 195, and 235 (1).…”

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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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Section: Chemotaxis Assaymentioning

confidence: 99%

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confidence: 99%

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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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“…LAT knock-in mice in which either the PLC-γ-binding tyrosine or the adapter-binding three distal tyrosines were mutated exhibited a polyclonal lymphoproliferation of CD4 + /TCRαβ or CD4 + /TCRγδ T cells, respectively, that secreted exaggerated levels of TH2 cytokines. Consequently, serum IgG1 and IgE were markedly increased, and peripheral tissues were infiltrated with eosinophils [31,32]. LAT mutations therefore unraveled that, besides positive signals, LAT supports negative signals that normally control terminal T cell differentiation and proliferation.…”

Section: Signaling Molecules In Negative Regulationmentioning

confidence: 98%

Regulation of allergy by Fc receptors

Bruhns

Frémont

Daëron

2005

Current Opinion in Immunology

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SummaryThe aggregation of high-affinity IgE receptors (FcεRI) on mast cells and basophils has long been known to be the critical event that initiates allergic reactions. Monomeric IgE was recently found to induce a variety of effects when binding to FcεRI. Up-regulation of FcεRI required binding only, whereas other responses resulted from FcεRI aggregation. Interestingly, FcεRI aggregation has been understood to generate a mixture of positive and negative intracellular signals. Mast cells/basophils express also low-affinity and, under specific conditions, high-affinity IgG receptors. When co-engaging these receptors with FcεRI, IgG antibodies can amplify or dampen IgE-induced mast cell activation. Based on these findings, FcRs have been proposed to be used as targets and/or tools for new therapeutic approaches of allergies.

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“…The Lat Inv targeting vector was cloned using a genomic fragment, isolated from 129/Ola phage library, containing a point mutation resulting in the substitution of the tyrosine 136 codon by a phenylalanine codon in exon 7 [31]. The 5 0 loxP511 site was inserted in a targeting vector by PCR mediated two-step mutagenesis using 490 bp EcoNI fragment as template.…”

Section: Generation Of Lat Inv Micementioning

confidence: 99%

Peripheral Thy1⁺ lymphocytes rearranging TCR‐γδ genes in LAT‐deficient mice

et al. 2009

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Linker for activation of T cells (LAT) is an adaptor molecule indispensable for development of ab and cd T lymphocytes. Surprisingly, using a new model of LAT-deficient mice we found that despite arrested thymic development, a discrete population of cells with active Lat promoter, expressing Thy1 molecules, accumulated in peripheral lymphoid organs of homozygous (Lat Inv/Inv ) mutant mice. By measuring frequencies of TCR gene rearrangements in conjunction with a panel of cell surface Ag, we dissected two subsets of these Thy1 1 cells. Thy1 dull cells expressed markers of NK lymphocytes and contained low frequency of TCR-c gene rearrangements without detectable TCR-d rearrangements. Thy1 high cells resembled immature CD44 1 CD25 1 thymocytes and contained high frequency of non-productive TCR-c and TCR-d rearrangements, indicating that cells displaying molecular signatures of commitment toward cd T-cell lineage can develop and populate lymphoid tissues of LAT-deficient mice. Phenotypically similar Thy1 high cells were also found in lymph nodes of lymphocyte-deficient (Rag2 À/À ) mice but not in T lymphocyte proficient, heterozygous Lat 1/Inv mice suggesting that Thy1 high cells of LAT-deficient mice identified in this study accumulate in peripheral lymphoid organs as a result of congenital lymphopenia.Key words: Extrathymic lymphopoiesis . LAT . Thymopoiesis . Thy1 . g/d T cells Supporting Information available online IntroductionLinker for activation of T cells (LAT) belongs to a family of transmembrane adaptor proteins involved in transduction of immunoreceptor-mediated signals [1,2].It is expressed in a number of hematopoietic cell lineages including T cells [3], pre-B cells [4], NK lymphocytes [5], megakaryocytes [6] and mast cells [7]. However, physiological roles of LAT adaptor in these cell lineages seem variable. In LAT knockout mice, NK lymphocytes, megakaryocytes and mast cells show seemingly normal development [8] with only discrete deficiencies of particular signaling pathways [5][6][7]. During B-cell maturation LAT deficiency causes a partial developmental block at the pre-B-cell stage [9,10]. In contrast, development of ab and gd T cells is entirely dependent on LAT adaptor, which is essential for signaling at the pre-TCR and ''TCR-gd quality control'' checkpoints [8,11]. Neither ab nor gd T cells have previously been found to develop and/or colonize the periphery of LAT knockout mice.In the thymus the incoming earliest CD4 À CD8 À double negative (DN) T-cell precursors progress through discrete 2596developmental stages, which may be characterized by cell surface expression of c-kit (CD117), CD25 and CD44 molecules and rearrangement status of g,. Transitions from the most immature and heterogeneous DN1 stage (c-kit high CD25 À CD44 1 ) through DN2 stage (c-kit int CD25 1 CD44 1 ) toward DN3 stage (c-kit low CD25 1 CD44 À ) are TCR independent, since only at DN3 stage most cells committed to T-cell lineages express TCR/CD3 complexes and undergo gd or b selection resulting in transition to DN4 (c-kit...

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Induction of T Helper Type 2 Immunity by a Point Mutation in the LAT Adaptor

Cited by 254 publications

References 25 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

Regulation of allergy by Fc receptors

Peripheral Thy1⁺ lymphocytes rearranging TCR‐γδ genes in LAT‐deficient mice

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Induction of T Helper Type 2 Immunity by a Point Mutation in the LAT Adaptor

Cited by 254 publications

References 25 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

Regulation of allergy by Fc receptors

Peripheral Thy1+ lymphocytes rearranging TCR‐γδ genes in LAT‐deficient mice

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Product

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Peripheral Thy1⁺ lymphocytes rearranging TCR‐γδ genes in LAT‐deficient mice