Research Publications

Back

A critical epithelial survival axis regulated by MCL-1 maintains thymic function in mice


Jain, R; Sheridan, JM; Policheni, A; Heinlein, M; Gandolfo, LC; Dewson, G; Smyth, GK; Sansom, SN; Fu, NY; Visvader, JE; Hollander, GA; Strasser, A; Gray, DHD
2017-09-29
Blood
Journal Article
130
23
2504-2515
T cell differentiation is governed by interactions with thymic epithelial cells (TECs) and defects in this process undermine immune function and tolerance. To uncover new strategies to restore thymic function and adaptive immunity in immunodeficiency, we sought to determine the molecular mechanisms that control life and death decisions in TEC. Guided by gene expression profiling, we created mouse models which specifically deleted pro-survival genes in TEC. We found that while BCL-2 and BCL-XL were dispensable for TEC homeostasis, MCL-1 deficiency impacted on TEC as early as E15.5, resulting in early thymic atrophy and T cell lymphopenia, with near complete loss of thymic tissue by 2 months of age. MCL-1 was not necessary for TEC differentiation but was continually required for the survival of mature cortical and medullary TEC, and the maintenance of thymic architecture. A screen of TEC trophic factors in organ cultures showed that epidermal growth factor (EGF) upregulated MCL-1 via MAPK/ERK kinase activity, providing a molecular mechanism for the support of TEC survival. This signalling axis governing TEC survival and thymic function represents a new target for strategies for thymic protection and regeneration.
ASH
Molecular Genetics of Cancer; Bioinformatics; Cell Signalling and Cell Death; Stem Cells and Cancer
10.1182/blood-2017-03-771576
28972012
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

Back
Creation Date 2017-10-16 02:00:01 Last Modified 2017-12-20 02:57:13