title: Tec family kinases modulate thresholds for thymocyte development and selection.
abstract: Tec family kinases are implicated in T cell receptor (TCR) signaling, and combined mutation of inducible T cell kinase (Itk) and resting lymphocyte kinase (Rlk)/Txk in mice dramatically impairs mature T cell function. Nonetheless, mutation of these kinases still permits T cell development. While itk(-)(/)- mice exhibit mild reductions in T cells with decreased CD4/CD8 cell ratios, rlk(-)(/)-itk(-)(/)- mice have improved total T cell numbers yet maintain decreased CD4/CD8 ratios. Using TCR transgenics and an in vitro thymocyte deletion model, we demonstrate that mutation of Tec kinases causes graded defects in thymocyte selection, leading to a switch from negative to positive selection in rlk(-)(/)-itk(-)(/)- animals. The reduction in both positive and negative selection and decreased CD4/CD8 ratios correlates with decreased biochemical parameters of TCR signaling, specifically defects in capacitive Ca(2+) influx and activation of the mitogen-activated kinases extracellular signal-regulated kinase 1 and 2. Thus, Tec kinases influence cell fate determination by modulating TCR signaling, leading to altered thresholds for thymocyte selection. These results provide support for a quantitative model for thymic development and provide evidence that defects in negative selection can substantially alter thymic cellularity.
authors.affiliation: National Human Genome Research Institute, Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Schaeffer
authors.forename: C
authors.initials: C
authors.lastname: Broussard
authors.forename: J
authors.initials: J
authors.lastname: Debnath
authors.forename: S
authors.initials: S
authors.lastname: Anderson
authors.forename: D W
authors.initials: DW
authors.lastname: McVicar
authors.forename: P L
authors.initials: PL
authors.lastname: Schwartzberg
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D005260:Female; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology
chemical_list: C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase