title: Ikaros is required to survive positive selection and to maintain clonal diversity during T-cell development in the thymus.
abstract: The zinc-finger protein Ikaros is a key player in T-cell development and a potent tumor suppressor in thymocytes. To understand the molecular basis of its function, we disabled Ikaros activity in vivo using a dominant negative Ikaros transgene (DN-IkTg). In DN-IkTg mice, T-cell development was severely suppressed, and positively selected thymocytes clonally expanded, resulting in a small thymus with a heavily skewed T-cell receptor (TCR) repertoire. Notably, DN-IkTg induced vigorous proliferation concomitant to downregulation of antiapoptotic factor expression such as Bcl2. Ikaros activity was required during positive selection, and specifically at the CD4(+)CD8(lo) intermediate stage of thymocyte differentiation, where it prevented persistent TCR signals from inducing aberrant proliferation and expansion. In particular, DN-IkTg induced the accumulation of CD4 single-positive (SP) thymocytes with a developmentally transitional phenotype, and it imposed a developmental arrest accompanied by massive apoptosis. Thus, we identified an in vivo requirement for Ikaros function, which is to suppress the proliferative potential of persistent TCR signals and to promote the survival and differentiation of positively selected thymocytes.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; and.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Tinsley
authors.forename: Changwan
authors.initials: C
authors.lastname: Hong
authors.forename: Megan A
authors.initials: MA
authors.lastname: Luckey
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Kim
authors.forename: Hee-Won
authors.initials: HW
authors.lastname: Yoon
authors.forename: Hilary R
authors.initials: HR
authors.lastname: Keller
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sacks
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Park
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
chemical_list: C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor
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