Defective Fas ligand expression and activation-induced cell death in the absence of IL-2-inducible T cell kinase.
The Tec family tyrosine kinase, IL-2-inducible T cell kinase (Itk), plays an important role in TCR signaling. Studies of T cells from Itk-deficient mice have demonstrated that Itk is critical for the activation of phospholipase-Cgamma1, leading to calcium mobilization in response to TCR stimulation. This biochemical defect results in reduced IL-2 production by Itk-deficient T cells. To further characterize the downstream effects of the Itk deficiency, we crossed Itk-/- mice to a TCR-transgenic line and examined T cell responses to stimulation by peptide plus APC. These studies show that Itk is required for maximal activation of early growth responses 2 and 3 and Fas ligand transcription after TCR stimulation. These transcriptional defects lead to reduced activation-induced cell death of stimulated Itk-/- T cells, both in vitro and in vivo. Together these studies define an important role for Itk in TCR signaling, leading to cytokine gene expression and activation-induced cell death.
Miller
Andrew T
AT
Department of Pathology, Program in Immunology and Virology, University of Massachusetts Medical Center, 55 Lake Avenue North, Worcester, MA 01655, USA.
Berg
Leslie J
LJ
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000276:immunology; D053222:Fas Ligand Protein; D019672:Genes, T-Cell Receptor; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation
D003574:Cytochrome c Group; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium