T cells are the major organizers of the adaptive immune response, and a target of viruses, such as HIV and HTLV-1, that cause currently incurable diseases. T cells develop from hematopoeitic stem cells that reside in the bone marrow. This process is governed by incompletely understood gene regulatory mechanisms that execute the T cell genetic program.
Our laboratory investigates gene regulation during T cell development. We use both in vivo transgenic mouse models as well as newly developed technology for in vitro T cell development from embryonic stem cells. Our focus has been on the regulation of the gene locus encoding the alpha chain of the T cell receptor (TCRa), particularly its locus control region (LCR). The TCRa LCR has powerful properties that provide a linked gene with a predictable pattern of gene expression in terms of level, developmental timing and cell-type distribution. It also bears a strong, but poorly understood, insulation capacity that provides LCR-linked transgenes with integration site-independence when inserted into the genome. Our work to date has identified numerous sub-sequences of the TCRa LCR that support its various properties. Molecular investigations of these sequence elements (and their interactions) are expected to reveal components required for completion of T cell development. It will also provide tools to establish robust, predictable and reliable therapeutic gene expression in T cells via eventual gene therapy applications.
Gomos-Klein J, Harrow F, Alarcon J, Ortiz BD. CTCF-independent, but not CTCF-dependent, elements significantly contribute to TCR-alpha locus control region activity. J Immunol. 2007 Jul 15;179(2):1088-95.
Harrow F, Ortiz BD. The TCRalpha locus control region specifies thymic, but not peripheral, patterns of TCRalpha gene expression. J Immunol. 2005 Nov 15;175(10):6659-67.
Harrow F, Amuta JU, Hutchinson SR, Akwaa F, Ortiz BD. Factors binding a non-classical Cis-element prevent heterochromatin effects on locus control region activity. J Biol Chem. 2004 Apr 23;279(17):17842-9.