Histone Acetyltransferase CBP Is Vital To Demarcate Conventional and Innate CD8⁺ T-Cell Development

Abstract

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.

SUPPLEMENTAL MATERIAL

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

ACKNOWLEDGMENTS

We thank J. Opferman for advice; S. Lerach, M. Biesen, and M. Castor for excellent technical assistance; and M. Paktinat for flow cytometry. We also thank the SJCRH Flow Cytometry and Cell Sorting Shared Resource; we thank R. Cross, J. Gatewood, and J. Rogers and the mouse immunophenotyping services in the Department of Immunology and the Animal Resource Center. The Hartwell Center at SJCRH provided oligonucleotides.

This work was supported by NIH grant R01 CA076385 (P.K.B.), a Cancer Center (CORE) support grant P30 CA021765, and the American Lebanese Syrian Associated Charities of SJCRH.

We do not have any conflicts of interest to declare.