title: Modulation of coreceptor transcription during positive selection dictates lineage fate independently of TCR/coreceptor specificity.
abstract: For developing T cells, coreceptor choice is matched to T cell antigen receptor (TCR) MHC specificity during positive selection in the thymus, but the mechanism remains uncertain. Here, we document that TCR-mediated positive selection signals inactivate the immature CD8(III) enhancer in double positive (DP) thymocytes, explaining in part the cessation of CD8 coreceptor transcription that occurs during positive selection. More importantly, by placing CD4 protein expression under the control of CD8 transcriptional regulatory elements, we demonstrate that cessation of CD4 coreceptor transcription during positive selection results in precisely the same lineage fate as cessation of CD8 coreceptor transcription. That is, MHC-II-signaled DP thymocytes differentiated into CD8-lineage cytotoxic T cells, despite the MHC-II specificity and CD4 dependence of their TCRs. This study demonstrates that termination of coreceptor transcription during positive selection promotes CD8-lineage fate, regardless of TCR specificity or coreceptor protein identity.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Sophia D
authors.initials: SD
authors.lastname: Sarafova
authors.forename: Batu
authors.initials: B
authors.lastname: Erman
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.forename: François
authors.initials: F
authors.lastname: Van Laethem
authors.forename: Terry
authors.initials: T
authors.lastname: Guinter
authors.forename: Susan O
authors.initials: SO
authors.lastname: Sharrow
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: Wildt
authors.forename: Wilfried
authors.initials: W
authors.lastname: Ellmeier
authors.forename: Alfred
authors.initials: A
authors.lastname: Singer
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000235:genetics*; D016827:CD8 Antigens / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology; D014158:Transcription, Genetic; D019076:Transgenes
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell