The role of HEB and E2A in the regulation of T Lymphocyte development and proliferation

dc.contributor.advisor

Zhuang,Yuan

dc.contributor.advisor

Krangel, Michael

dc.contributor.advisor

Kelsoe, Garnett

dc.contributor.advisor

Zhang, Weiguo

dc.contributor.advisor

Shieh, Tao

dc.contributor.author

Wojciechowski, Jason

dc.date.accessioned

2007-05-10T16:02:36Z

dc.date.available

2007-05-10T16:02:36Z

dc.date.issued

2007-05-10T16:02:36Z

dc.department

Immunology

dc.description.abstract

Thymocyte development is a complex process that requires precise regulation of differentiation and proliferation. Basic helix-loop-helix (bHLH) transcription factors have been shown to be crucial for proper T cell development. HEB and E2A are structurally and functionally related E proteins of the bHLH family. These proteins directly regulate the expression of a number of genes essential for lymphocyte development in a lineage- and stage-specific manner. Abrogation or compromise of their function results in the manifestation of B and T cell developmental defects. Genetic and biochemical studies have provided evidence of a significant degree of functional redundancy among E proteins. The existence of compensational abilities among different E proteins has hampered the investigation and elucidation of E protein function. As such, single gene knockouts demonstrate only limited defects in lymphocyte development. Double E2A-HEB knockouts that could eliminate E protein redundancy are embryonic lethal. In addition, conventional gene knockouts are not well-suited for discerning between intrinsic and extrinsic defects caused by E protein disruption. To eliminate functional compensation and to test the T cell intrinsic roles of E proteins during thymocyte development, we developed a conditional HEB-E2A double knockout. Specifically, we employed a loxP/Lck-Cre recombinase system to drive E protein deletion during early thymocyte development. Using this approach, we were able to reveal overlapping roles for HEB and E2A in thymocyte development that had been obscured in previous single gene knockout studies. We find that simultaneous deletion of HEB and E2A results in a severe block in thymocyte development at the DN to DP stage transition. This developmental block is accompanied by a dramatic decrease in total thymic cellularity, an increase in apoptosis, and a reduction of pTα expression. These developmentally arrested thymocytes exhibit increased proliferation in vivo and dramatic expansion ex vivo in response to IL-7 signaling. Our findings suggest that E2A and HEB are not only critical for the regulation of T cell differentiation but are also necessary to retain developing thymocytes in cell cycle arrest prior to pre-TCR expression. Together, these results imply that E proteins are required to coordinate thymocyte differentiation and proliferation.

dc.format.extent

3494589 bytes

dc.format.mimetype

application/pdf

dc.identifier.uri

https://hdl.handle.net/10161/214

dc.language.iso

en_US

dc.subject

E2A

dc.subject

HEB

dc.subject

T cell development

dc.subject

Transcription factor

dc.title

The role of HEB and E2A in the regulation of T Lymphocyte development and proliferation

dc.type

Dissertation

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
D_Wojciechowski_Jason_a_052007.pdf
Size:
3.33 MB
Format:
Adobe Portable Document Format

Collections