T cell receptor (TCR) gene rearrangement through V(D)J recombination provides the structural basis for adaptive immunity. This gene rearrangement event is unique to the lymphoid system and yields a rich repertoire of T cells which are capable of recognizing a diverse array of peptide antigens during immune responses. Very little is known about the regulatory molecules that control the precise timing and selectivity of transcription of individual TCR genes during T cell development in the thymus. Recent works have shown that the transcription factors E2A and HEB play important roles in initiating lymphoid specific V(D)J recombination events. Genetic studies carried out in our own laboratory further suggested that E2A/HEB are directly involved in gene rearrangement at the TCR beta locus. In this proposal, we plan to specifically investigate the role of E2A/HEB in TCR beta gene transcription and rearrangement during T cell development. First, we hypothesize that E2A and HEB transcription factors are directly involved in TCR V beta gene transcription to ensure that all the V genes have a chance to be used in rearrangement. Second, this E2A/HEB activity must be down regulated subsequently at the DP stage to prevent biallelic expression of the TCR beta gene, a process known as allelic exclusion. We have developed several mouse models to allow both genetic and biochemical investigations of E2A/HEB function in T cell development. In particular, an E2A knockin mouse expressing tagged E2A molecules will be used in chromatin immunoprecipitation assays to determine where and when E2A functions in the TCR beta locus. Gene knockout mice will be used to determine the causal link between E2A/HEB and TCR gene expression. While the proposed research focuses on the dissection of TCR beta gene locus, the methods and concepts are generally applicable to understanding other E2A/HEB target genes identified in T cells. Most E2A/HEB targets, including TCR beta, preT alpha, and TCR alpha genes, must be coordinately expressed to ensure the proper progression and completion of T cell development. Thus, we will also conduct a genome-based study to broaden our understanding of the coordinate gene regulation events during T cell development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059638-06
Application #
6829673
Study Section
Immunobiology Study Section (IMB)
Program Officer
Marino, Pamela
Project Start
1999-08-01
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
6
Fiscal Year
2005
Total Cost
$315,700
Indirect Cost
Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Zhang, Baojun; Jiao, Anjun; Dai, Meifang et al. (2018) Id3 Restricts ?? NKT Cell Expansion by Controlling Egr2 and c-Myc Activity. J Immunol 201:1452-1459
Roy, Sumedha; Moore, Amanda J; Love, Cassandra et al. (2018) Id Proteins Suppress E2A-Driven Invariant Natural Killer T Cell Development prior to TCR Selection. Front Immunol 9:42
Carico, Zachary M; Roy Choudhury, Kingshuk; Zhang, Baojun et al. (2017) Tcrd Rearrangement Redirects a Processive Tcra Recombination Program to Expand the Tcra Repertoire. Cell Rep 19:2157-2173
Li, Jia; Roy, Sumedha; Kim, Young-Mi et al. (2017) Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors. J Immunol 198:3136-3148
Zhang, Baojun; Jia, Qingzhu; Bock, Cheryl et al. (2016) Glimpse of natural selection of long-lived T-cell clones in healthy life. Proc Natl Acad Sci U S A 113:9858-63
Zhang, Baojun; Wu, Jianxuan; Jiao, Yiqun et al. (2015) Differential Requirements of TCR Signaling in Homeostatic Maintenance and Function of Dendritic Epidermal T Cells. J Immunol 195:4282-91
Roy, Sumedha; Zhuang, Yuan (2015) Orchestration of invariant natural killer T cell development by E and Id proteins. Crit Rev Immunol 35:33-48
Belle, Ian; Zhuang, Yuan (2014) E proteins in lymphocyte development and lymphoid diseases. Curr Top Dev Biol 110:153-87
Belle, Ian; Mahlios, Josh; McKenzie, Andrew et al. (2014) Aberrant production of IL-13 by T cells promotes exocrinopathy in Id3 knockout mice. Cytokine 69:226-33
Zhang, Baojun; Lin, Yen-Yu; Dai, Meifang et al. (2014) Id3 and Id2 act as a dual safety mechanism in regulating the development and population size of innate-like ?? T cells. J Immunol 192:1055-1063

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