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

Author(s): 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;
Details: Publication Year 2017-09-29,Volume 130,Issue #23,Page 2504-2515
Journal Title: Blood
Publication Type: Journal Article
Abstract: 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.
Publisher: ASH
Research Division(s): Molecular Genetics Of Cancer; Bioinformatics; Cell Signalling And Cell Death; Stem Cells And Cancer
PubMed ID: 28972012
Publisher's Version: https://doi.org/10.1182/blood-2017-03-771576
NHMRC Grants: NHMRC/1020363, NHMRC/1086727, NHMRC/1090236,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-10-16 02:00:01

Last Modified: 2017-12-20 02:57:13