Abstract
LAT (linker for activation of T cells) is a transmembrane adaptor protein that plays an essential role in TCR-mediated signaling and thymocyte development. Because LAT-deficient mice have an early block in thymocyte development, we utilized an inducible system to delete LAT in primary T cells to study LAT function in T cell activation, homeostasis, and survival. Deletion of LAT caused primary T cells to become unresponsive to stimulation from the TCR and impaired T cell homeostatic proliferation and long term survival. Furthermore, deletion of LAT led to reduced expression of Foxp3, CTLA-4, and CD25 in T(reg) cells and impaired their function. Consequently, mice with LAT deleted developed a lymphoproliferative syndrome similar to that in LATY136F mice, although less severe. Our data implicate that LAT has positive and negative roles in the regulation of mature 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 / immunology*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Autoimmune Lymphoproliferative Syndrome / genetics
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Autoimmune Lymphoproliferative Syndrome / immunology
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Autoimmune Lymphoproliferative Syndrome / metabolism
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Blotting, Western
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cell Survival / immunology
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Female
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Flow Cytometry
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Forkhead Transcription Factors / immunology
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Forkhead Transcription Factors / metabolism
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Homeostasis / drug effects
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Homeostasis / immunology*
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology*
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Male
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Membrane Proteins / genetics
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Membrane Proteins / immunology*
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Phosphoproteins / genetics
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Phosphoproteins / immunology*
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Phosphoproteins / metabolism
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction / immunology
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Spleen / cytology
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Spleen / immunology
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Spleen / metabolism
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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Tamoxifen / pharmacology
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Thymus Gland / cytology
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Thymus Gland / immunology
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Thymus Gland / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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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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Tamoxifen