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Ikaros is required to survive positive selection and to maintain clonal diversity during T-cell development in the thymus

Cited 8 time in Web of Science Cited 8 time in Scopus
Authors

Tinsley, Kevin W.; Hong, Changwan; Luckey, Megan A.; Park, Joo-Young; Kim, Grace Y.; Yoon, Hee-won; Keller, Hilary R.; Sacks, Andrew J.; Feigenbaum, Lionel; Park, Jung-Hyun

Issue Date
2013-10
Publisher
American Society of Hematology
Citation
Blood, Vol.122 No.14, pp.2358-2368
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.
ISSN
0006-4971
URI
https://hdl.handle.net/10371/202764
DOI
https://doi.org/10.1182/blood-2012-12-472076
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