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Notch signaling pathway keeps immature T cells on the right track

Date:
November 22, 2013
Source:
Perelman School of Medicine at the University of Pennsylvania
Summary:
One protein called Notch, which has well-known roles in the development of multiple tissues, plays an essential role in triggering T-cell development. Notch signaling induces expression of genes that promote the maturation of T cells and discourage alternative cell fates. Deficiency of the Notch target gene Hes1 in blood stem cells results in extremely low T-cell numbers, and could shed light on how normal cells are transformed in the context of cancer.
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The lab of Avinash Bhandoola, PhD, professor of Pathology and Laboratory Medicine, has studied the origins of T cells for many years. One protein called Notch, which has well-known roles in the development of multiple tissues, plays an essential role in triggering T-cell development. T cells are immune cells that are made in the thymus, a small organ situated under the breastbone near the heart. However, T cells, like all blood-cell types, originate from blood-producing stem cells in the bone marrow. Immature T-cell progenitors leave the bone marrow, settle within the thymus, and eventually give rise to T cells.

With graduate student Maria Elena De Obaldia, Bhandoola describes in Nature Immunology this month how Notch signaling induces expression of genes that promote the maturation of T cells and discourage alternative cell fates. Deficiency of the Notch target gene Hes1 in blood stem cells results in extremely low T-cell numbers, but the underlying mechanism is unknown. Keeping in mind that Notch signaling gone awry induces leukemia, De Obaldia notes that "understanding the Notch pathway on a molecular level can shed light on how normal cells are transformed in the context of cancer."

The current study describes the mechanism of action of Hes1, a repressor protein that acts in the nucleus of immature T cells in the thymus. De Obaldia and Bhandoola found that Hes1 turns off genes such as C/EBPalpha, which promote the myeloid-cell fate and antagonize the T-cell fate. Whereas Hes1-deficient mice show severe T-cell defects, deleting the myeloid gene C/EBPalpha could restore normal T-cell development. This provided evidence that Hes1 keeps immature T cells on track by preventing them from defaulting to a myeloid developmental pathway, which controls non-lymphocyte cell maturation.

Because of this "policing" function, De Obaldia likens Hes1 to the traffic cop of T-cell development: "T-cell leukemias are addicted to Hes1, perhaps because it keeps progenitor cells on the path to producing more T cells, as opposed to myeloid cells. Bhandoola adds, "Our findings establish the importance of constraining myeloid developmental programs early in T-cell development, and this knowledge may provide clues about how to stop T-cell leukemias." Future studies will address whether Hes1 serves a similar function in Notch-dependent, T-cell leukemias by repressing myeloid genes, as it does during normal T-cell development.


Story Source:

The above post is reprinted from materials provided by Perelman School of Medicine at the University of Pennsylvania. Note: Materials may be edited for content and length.


Journal Reference:

  1. Maria Elena De Obaldia, J Jeremiah Bell, Xinxin Wang, Christelle Harly, Yumi Yashiro-Ohtani, Jonathan H DeLong, Daniel A Zlotoff, Dil Afroz Sultana, Warren S Pear, Avinash Bhandoola. T cell development requires constraint of the myeloid regulator C/EBP-α by the Notch target and transcriptional repressor Hes1. Nature Immunology, 2013; 14 (12): 1277 DOI: 10.1038/ni.2760

Cite This Page:

Perelman School of Medicine at the University of Pennsylvania. "Notch signaling pathway keeps immature T cells on the right track." ScienceDaily. ScienceDaily, 22 November 2013. <www.sciencedaily.com/releases/2013/11/131122165451.htm>.
Perelman School of Medicine at the University of Pennsylvania. (2013, November 22). Notch signaling pathway keeps immature T cells on the right track. ScienceDaily. Retrieved August 31, 2015 from www.sciencedaily.com/releases/2013/11/131122165451.htm
Perelman School of Medicine at the University of Pennsylvania. "Notch signaling pathway keeps immature T cells on the right track." ScienceDaily. www.sciencedaily.com/releases/2013/11/131122165451.htm (accessed August 31, 2015).

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