LAT regulates γδ T cell homeostasis and differentiation

Nuñez-Cruz, Selene; Aguado, Enrique; Richelme, Sylvie; Chetaille, Bruno; Mura, Anne-Marie; Richelme, Mireille; Pouyet, Laurent; Jouvin‐Marche, Evelyne; Xerri, Luc; Malissen, Bernard; Malissen, Marie

doi:10.1038/ni977

Cited by 108 publications

(127 citation statements)

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“…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). The LatY136F CD4 ϩ ␣␤ T cells and Lat3YF ␥␦ T cells had both a CD25 Ϫ CD44 high CD62L low CD69 ϩ phenotype closely resembling that of activated effector and memory T cells.…”

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confidence: 99%

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: 99%

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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“…Thy1 1 cells were previously observed in spleens of LAT-deficient mice, but their origin and characteristics have not been investigated [26]. In the present study, we characterized peripheral Thy1 1 cells identified in a new model of LAT-deficient mice in which ECFP expression reflects physiological pattern of LAT expression.…”

Section: Discussionmentioning

confidence: 88%

“…For PCR reactions, 20 ng of template genomic DNA was used and cycling protocols were exactly as described [13,34]. The primer sequences for Vg2, Vg3, Vg4, Jg1, Jg2, Jg4, Vd1, Vd4, Vd5, Vd6, Jd1, and sequences of probes for Jg1, Jg2, Jg4 and Jd1 rearrangements detection were described previously [13]; primers for Db2, Jb2 and Jb2 probe were described in [26]. The oligonucleotide probes for Jg1, Jd1 and Jb2 were 3 0 end labeled with Digoxigenin.…”

Section: Detection Of Tcr Rearrangementsmentioning

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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“…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: 99%

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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LAT regulates γδ T cell homeostasis and differentiation

Cited by 108 publications

References 49 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

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

Regulation of allergy by Fc receptors

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LAT regulates γδ T cell homeostasis and differentiation

Cited by 108 publications

References 49 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

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

Regulation of allergy by Fc receptors

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