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Molecular and Cellular Biology, July 2009, p. 3894-3904, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.01598-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Histone Acetyltransferase CBP Is Vital To Demarcate Conventional and Innate CD8+ T-Cell Development{triangledown} ,{dagger}

Tomofusa Fukuyama,1 Lawryn H. Kasper,1 Fayçal Boussouar,1 Trushar Jeevan,1 Jan van Deursen,2 and Paul K. Brindle1*

Department of Biochemistry, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105,1 Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, Minnesota 559052

Received 12 October 2008/ Returned for modification 5 December 2008/ Accepted 4 May 2009

Defining the chromatin modifications and transcriptional mechanisms that direct the development of different T-cell lineages is a major challenge in immunology. The transcriptional coactivators CREB binding protein (CBP) and the closely related p300, which comprise the KAT3 family of histone/protein lysine acetyltransferases, interact with over 50 T-lymphocyte-essential transcriptional regulators. We show here that CBP, but not p300, modulates the thymic development of conventional adaptive T cells versus those having unconventional innate functions. Conditional inactivation of CBP in the thymus yielded CD8 single-positive (SP) thymocytes with an effector-, memory-, or innate-like T-cell phenotype. In this regard, CD8 SP thymocytes in CBP mutant mice were phenotypically similar to those reported for Itk and Rlk protein tyrosine kinase mutants, including the increased expression of the T-cell master regulatory transcription factor eomesodermin (Eomes) and the interleukin-2 and -15 receptor beta chain (CD122) and an enhanced ability to rapidly produce gamma interferon. CBP was required for the expression of the Itk-dependent genes Egr2, Egr3, and Il2, suggesting that CBP helps mediate Itk-responsive transcription. CBP therefore defines a nuclear component of the signaling pathways that demarcate the development of innate and adaptive naïve CD8+ T cells in the thymus.

* Corresponding author. Mailing address: Department of Biochemistry, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105. Phone: (901) 595-2522. Fax: (901) 525-8025. E-mail: paul.brindle{at}stjude.org

{triangledown} Published ahead of print on 11 May 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, July 2009, p. 3894-3904, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.01598-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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