Requirement for Tec Kinases Rlk and Itk in T Cell Receptor Signaling and Immunity

• Published in: Science (American Association for the Advancement of Science) 1999-04, Vol.284 (5414), p.638-641
• Main Authors: Schaeffer, Edward M., Debnath, Jayanta, Yap, George, McVicar, Daniel, Liao, X. Charlene, Littman, Dan R., Sher, Alan, Varmus, Harold E., Lenardo, Michael J., Schwartzberg, Pamela L.
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Animals; Antigen presenting cells; Antigen receptors, T cell; Apoptosis; Biological and medical sciences; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; CD4-CD8 Ratio; Cell growth; Cellular biology; Diglycerides - metabolism; Enzymes; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Targeting; Immunity; Immunobiology; Infections; Inositol Phosphates - metabolism; Interferon-gamma - biosynthesis; Interleukin-2 - biosynthesis; Interleukin-2 - pharmacology; Isoenzymes - metabolism; Killer Cells, Natural - immunology; Lymphocyte Activation; Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation; Mice; Mutation; Natural killer T cells; Numbers; Phospholipase C gamma; Phosphorylation; Protein tyrosine kinase; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Receptors; Receptors, Antigen, T-Cell - metabolism; Signal Transduction; Splenocytes; T cell antigen receptors; T cells; T lymphocytes; T-Lymphocytes - enzymology; T-Lymphocytes - immunology; Toxoplasmosis, Animal - immunology; Type C Phospholipases - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.284.5414.638

T cell receptor (TCR) signaling requires activation of Zap-70 and Src family tyrosine kinases, but requirements for other tyrosine kinases are less clear. Combined deletion in mice of two Tec kinases, Rlk and Itk, caused marked defects in TCR responses including proliferation, cytokine production, and apoptosis in vitro and adaptive immune responses to Toxoplasma gondii in vivo. Molecular events immediately downstream from the TCR were intact in rlk$^{-/-}$itk$^{-/-}$ cells, but intermediate events including inositol trisphosphate production, calcium mobilization, and mitogen-activated protein kinase activation were impaired, establishing Tec kinases as critical regulators of TCR signaling required for phospholipase C-γ activation.