Abstract
The interaction between the linker for activation of T cells (LAT) with PLC-gamma1 is important for TCR-mediated Ca(2+) signaling and MAPK activation. Knock-in mice harboring a mutation at the PLC-gamma1 binding site (Y136) of LAT develop a severe lymphoproliferative syndrome. These mice have defective thymic development and selection and lack natural regulatory T cells, implicating a breakdown of both central and peripheral tolerance. To bypass this developmental defect, we developed a conditional knock-in line in which only LATY136F is expressed in mature T cells after deletion of the wild type LAT allele. Analysis of LATY136F T cells indicated that the interaction between LAT and PLC-gamma1 plays an important role in TCR-mediated signaling, proliferation, and IL-2 production. Furthermore, the deletion of LAT induced development of the lymphoproliferative syndrome in these mice. Although Foxp3(+) natural Treg cells were present in these mice after deletion, they were unable to suppress the proliferation of conventional T cells. Our data indicate that the binding of LAT to PLC-gamma1 is essential for the suppressive function of CD4(+)CD25(+) regulatory T cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Adaptor Proteins, Signal Transducing / physiology*
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Animals
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Blotting, Western
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Female
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Flow Cytometry
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Gene Deletion
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Gene Knock-In Techniques
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Interleukin-2 / metabolism
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Lymphocyte Activation / immunology*
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Lymphoproliferative Disorders / genetics
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Lymphoproliferative Disorders / immunology
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Lymphoproliferative Disorders / pathology
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Membrane Proteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Phospholipase C gamma / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphoproteins / physiology*
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Phosphorylation
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Protein Binding
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / immunology
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Thymus Gland / immunology
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Thymus Gland / metabolism
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Thymus Gland / pathology
Substances
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Adaptor Proteins, Signal Transducing
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Interleukin-2
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Lat protein, mouse
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Membrane Proteins
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Phosphoproteins
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Receptors, Antigen, T-Cell
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Phospholipase C gamma