Journal article
A critical epithelial survival axis regulated by MCL-1 maintains thymic function in mice
R Jain, JM Sheridan, A Policheni, M Heinlein, LC Gandolfo, G Dewson, GK Smyth, SN Sansom, NY Fu, JE Visvader, GA Holländer, A Strasser, DHD Gray
Blood | AMER SOC HEMATOLOGY | Published : 2017
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 TECs. Guided by gene expression profiling, we created mouse models that specifically deleted prosurvival genes in TECs. We found that although BCL-2 and BCL-XL were dispensable for TEC homeostasis, MCL-1 deficiency impacted on TECs as early as embryonic day 15.5, resulting in early thymic atrophy and T-cell lymphopenia, with near complete loss of thymic tis..
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Awarded by University of Melbourne
Funding Acknowledgements
This work was supported by grants GNT0637353, GNT1049724, GNT1121325, and GNT1054618 and Career Development Fellowship-2 1090236 (D.H.D.G.), 1016701, Senior Principal Research Fellow Fellowship 1020363 (A.S.), Australia Fellowship (J.E.V.), GNT1086727 (N.Y.F.), and Fellowship 1058892 (G.K.S.) from the Australian National Health and Medical Research Council, Wellcome Trust 105045/Z/14/Z (G.A.H.), the Leukemia & Lymphoma Society of America (Specialized Center of Research grant 7001-13), the Leukaemia Research Foundation, and Melbourne International Research Scholarship and Melbourne International Fee Remission Scholarship (R.J.) from the University of Melbourne. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institute Infrastructure Support Scheme.