The absence of Itk inhibits positive selection without changing lineage commitment.
The Tec family tyrosine kinase Itk is critical for efficient signaling downstream of the TCR. Biochemically, Itk is directly phosphorylated and activated by Lck. Subsequently, Itk activates phospholipase C-gamma1, leading to calcium mobilization and extracellular signal-regulated kinase/mitogen-activated protein kinase activation. These observations suggested that Itk might play an important role in positive selection and CD4/CD8 lineage commitment during T cell development in the thymus. To test this, we crossed Itk-deficient mice to three lines of TCR transgenics and analyzed progeny on three different MHC backgrounds. Analysis of these mice revealed that fewer TCR transgenic T cells develop in the absence of Itk. In addition, examination of multiple T cell development markers indicates that multiple stages of positive selection are affected by the absence of Itk, but the T cells that do develop appear normal. In contrast to the defects in positive selection, CD4/CD8 lineage commitment seems to be intact in all the TCR transgenic itk(-/-) lines tested. Overall, these data indicate that altering TCR signals by the removal of Itk does not affect the appropriate differentiation of thymocytes based on their MHC specificity, but does impact the efficiency with which thymocytes complete their maturation process.
Lucas
Julie A
JA
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Atherly
Luana O
LO
Berg
Leslie J
LJ
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD; D015415:Biomarkers / Q000032:analysis; D015704:CD4 Antigens / Q000096:biosynthesis; D018956:CD5 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006183:H-2 Antigens / Q000096:biosynthesis; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000071176:Signaling Lymphocytic Activation Molecule Family; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000276:immunology
D015703:Antigens, CD; D015415:Biomarkers; D015704:CD4 Antigens; D018956:CD5 Antigens; C490007:Cd244a protein, mouse; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D008024:Ligands; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase