title: Ikaros null mice display defects in T cell selection and CD4 versus CD8 lineage decisions.
abstract: Previous evidence suggested that the hemopoietic-specific nuclear factor Ikaros regulates TCR signaling thresholds in mature T cells. In this study, we test the hypothesis that Ikaros also sets TCR signaling thresholds to regulate selection events and CD4 vs CD8 lineage determination in developing thymocytes. Ikaros null mice were crossed to three lines of TCR-transgenic mice, and positive selection, negative selection, and CD4 vs CD8 lineage decisions were analyzed. Mice expressing a polyclonal repertoire or a MHC class II-restricted TCR transgene exhibited enhanced positive selection toward the CD4 lineage. Moreover, in the absence of Ikaros, CD4 development can occur with decreased thresholds of TCR signaling. In addition, CD4 single-positive thymocytes were detected in MHC class I-restricted TCR-transgenic Ikaros null mice. To assess the role of Ikaros in negative selection, we analyzed deletion of T cells induced by conventional Ag or by endogenous superantigen. Surprisingly, negative selection was impaired in Ikaros null thymocytes despite evidence of high levels of TCR signal and no intrinsic defect in apoptosis ex vivo. To our knowledge, these data identify Ikaros as the first nuclear factor that plays a critical role in regulating negative selection as well as CD4 vs CD8 lineage decisions during positive selection.
authors.affiliation: Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Urban
authors.forename: Susan
authors.initials: S
authors.lastname: Winandy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D005260:Female; D006182:H-Y Antigen / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D051740:Ikaros Transcription Factor; D018655:Lymphocyte Count; D008297:Male; D008324:Mammary Tumor Virus, Mouse / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D018089:Superantigens / Q000096:biosynthesis / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
chemical_list: D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D006182:H-Y Antigen; D015395:Histocompatibility Antigens Class I; D018398:Homeodomain Proteins; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; C064658:RAG-1 protein; D051740:Ikaros Transcription Factor