The Importance of LAT in the Activation, Homeostasis, and Regulatory Function of T Cells

• Published in: The Journal of biological chemistry 2010-11, Vol.285 (46), p.35393-35405
• Main Authors: Shen, Shudan, Chuck, Mariana I., Zhu, Minghua, Fuller, Deirdre M., Yang, Chih-wen Ou, Zhang, Weiguo
• Format: Article
• Language: English
• Subjects: Adaptor Proteins; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - immunology; Adaptor Proteins, Signal Transducing - metabolism; Animals; Autoimmune Lymphoproliferative Syndrome - genetics; Autoimmune Lymphoproliferative Syndrome - immunology; Autoimmune Lymphoproliferative Syndrome - metabolism; Blotting, Western; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - immunology; Female; Flow Cytometry; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Homeostasis - drug effects; Homeostasis - immunology; Immunology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Male; Membrane Proteins - genetics; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mice; Mice, Knockout; Phosphoproteins - genetics; Phosphoproteins - immunology; Phosphoproteins - metabolism; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Signal Transduction; Signal Transduction - immunology; Spleen - cytology; Spleen - immunology; Spleen - metabolism; T-cell Receptor; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tamoxifen - pharmacology; Thymus Gland - cytology; Thymus Gland - immunology; Thymus Gland - metabolism; Tyrosine-protein Kinase (Tyrosine Kinase)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.145052

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 Treg 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.