title: Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection.
abstract: SHP1 is a tyrosine phosphatase critical to proximal regulation of TCR signaling. Here, analysis of CD4-Cre SHP1(fl/fl) conditional knockout thymocytes using CD53, TCRβ, CD69, CD4, and CD8α expression demonstrates the importance of SHP1 in the survival of post selection (CD53(+) ), single-positive thymocytes. Using Ca(2+) flux to assess the intensity of TCR signaling demonstrated that SHP1 dampens the signal strength of these same mature, postselection thymocytes. Consistent with its dampening effect, TCR signal strength was also probed functionally using peptides that can mediate selection of the OT-I TCR, to reveal increased negative selection mediated by lower-affinity ligand in the absence of SHP1. Our data show that SHP1 is required for the survival of mature thymocytes and the generation of the functional T-cell repertoire, as its absence leads to a reduction in the numbers of CD4(+) and CD8(+) naïve T cells in the peripheral lymphoid compartments.
authors.affiliation: Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Martinez
authors.affiliation: Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA.
authors.forename: Anna B
authors.initials: AB
authors.lastname: Morris
authors.affiliation: Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA.
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Neeld
authors.affiliation: Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA. bevavol@emory.edu.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Evavold
mesh_terms: D000818:Animals; D015415:Biomarkers; D060966:Clonal Selection, Antigen-Mediated / Q000235:genetics* / Q000276:immunology*; D005260:Female; D018390:Gene Targeting; D006649:Histocompatibility Antigens / Q000276:immunology / Q000378:metabolism; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000172:deficiency*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D006649:Histocompatibility Antigens; D011948:Receptors, Antigen, T-Cell; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse
keywords: SHP1; T-cell homeostasis; T-cell selection; TCR signaling; Thymocyte development