Within the thymus, Notch signals imprint T cell identity on multipotential hematopoietic progenitors. Notch signals must inhibit non-T cell fates (commitment) and drive T cell lineage-specific gene expression (specification), but the mechanisms have remained unclear. We recently identified T Cell Factor-1 (TCF-1) as the """"""""missing link"""""""" that coordinates T-lineage specific gene expression downstream of Notch signals. We further discovered that HES-1 is important for establishing T cell commitment in early T cell progenitors. We propose to investigate molecular mechanisms through which TCF-1 and HES-1 establish and maintain T cell identity.
In Aim 1, we will examine how HES-1 and TCF-1 together establish commitment to the T cell lineage. Because TCF-1 continues to be expressed after T cell commitment, we will investigate whether T-cell specific gene expression unravels if TCF-1 is ablated in committed T cell progenitors.
In Aim 2, we will establish the mechanisms by which TCF-1 acts in T cell development. We will identify the gene regulatory program controlled by TCF-1, and we will identify and study partners that work with TCF-1 to control gene expression. Studies in this proposal will improve our understanding of how T cells are generated and how T cell identity is maintained. They may inform therapeutic strategies to boost T cell development and reconstitution in immune deficiency and after bone marrow transplantation.

Public Health Relevance

Defects in T cell development may cause susceptibility to infections or leukemia development. We propose to identify the molecular mechanisms that control early T cell development. Our studies may lead to new therapeutic strategies to accelerate T-cell development in immune deficiency disorders and after bone marrow transplantation, and will also provide insights into how dysregulated T cell development can result in T cell leukemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI059621-11
Application #
8891711
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Prabhudas, Mercy R
Project Start
2004-03-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Yang, Qi; Li, Fengyin; Harly, Christelle et al. (2015) TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow. Nat Immunol 16:1044-50
De Obaldia, Maria Elena; Bhandoola, Avinash (2015) Transcriptional regulation of innate and adaptive lymphocyte lineages. Annu Rev Immunol 33:607-42
Rupp, Levi J; Brady, Brenna L; Carpenter, Andrea C et al. (2014) The microRNA biogenesis machinery modulates lineage commitment during αβ T cell development. J Immunol 193:4032-42
De Obaldia, Maria Elena; Bell, J Jeremiah; Wang, Xinxin et al. (2013) T cell development requires constraint of the myeloid regulator C/EBP-α by the Notch target and transcriptional repressor Hes1. Nat Immunol 14:1277-84
Yang, Qi; Monticelli, Laurel A; Saenz, Steven A et al. (2013) T cell factor 1 is required for group 2 innate lymphoid cell generation. Immunity 38:694-704
Weber, Brittany Nicole; Chi, Anthony Wei-Shine; Chavez, Alejandro et al. (2011) A critical role for TCF-1 in T-lineage specification and differentiation. Nature 476:63-8
Love, Paul E; Bhandoola, Avinash (2011) Signal integration and crosstalk during thymocyte migration and emigration. Nat Rev Immunol 11:469-77
Sultana, Dil Afroz; Bell, J Jeremiah; Zlotoff, Daniel A et al. (2010) Eliciting the T cell fate with Notch. Semin Immunol 22:254-60