title: TOX provides a link between calcineurin activation and CD8 lineage commitment.
abstract: T cell development is dependent on the integration of multiple signaling pathways, although few links between signaling cascades and downstream nuclear factors that play a role in thymocyte differentiation have been identified. We show here that expression of the HMG box protein TOX is sufficient to induce changes in coreceptor gene expression associated with beta-selection, including CD8 gene demethylation. TOX expression is also sufficient to initiate positive selection to the CD8 lineage in the absence of MHC-TCR interactions. TOX-mediated positive selection is associated with up-regulation of Runx3, implicating CD4 silencing in the process. Interestingly, a strong T cell receptor-mediated signal can modify this cell fate. We further demonstrate that up-regulation of TOX in double positive thymocytes is calcineurin dependent, linking this critical signaling pathway to nuclear changes during positive selection.
authors.affiliation: Department of Immunology IMM-8, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
authors.forename: Parinaz
authors.initials: P
authors.lastname: Aliahmad
authors.forename: Emmett
authors.initials: E
authors.lastname: O'Flaherty
authors.forename: Peggy
authors.initials: P
authors.lastname: Han
authors.forename: Olivia D
authors.initials: OD
authors.lastname: Goularte
authors.forename: Beverley
authors.initials: B
authors.lastname: Wilkinson
authors.forename: Masanobu
authors.initials: M
authors.lastname: Satake
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kaye
mesh_terms: D000818:Animals; D001483:Base Sequence; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism*; D002454:Cell Differentiation; D017931:DNA Primers / Q000235:genetics; D004789:Enzyme Activation; D020868:Gene Silencing; D024002:HMGB Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D017931:DNA Primers; D024002:HMGB Proteins; D011948:Receptors, Antigen, T-Cell; D019703:Calcineurin