MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival

The molecular mechanisms that underlie T-cell quiescence are poorly understood. In the present study, we report a primary immunodeficiency phenotype associated with MST1 deficiency and primarily characterized by a progressive loss of naive T cells. The in vivo consequences include recurrent bacteria...

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Veröffentlicht in:Blood 2012-04, Vol.119 (15), p.3458-3468
Hauptverfasser: Nehme, Nadine T., Schmid, Jana Pachlopnik, Debeurme, Franck, André-Schmutz, Isabelle, Lim, Annick, Nitschke, Patrick, Rieux-Laucat, Frédéric, Lutz, Patrick, Picard, Capucine, Mahlaoui, Nizar, Fischer, Alain, de Saint Basile, Geneviève
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Sprache:eng
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Zusammenfassung:The molecular mechanisms that underlie T-cell quiescence are poorly understood. In the present study, we report a primary immunodeficiency phenotype associated with MST1 deficiency and primarily characterized by a progressive loss of naive T cells. The in vivo consequences include recurrent bacterial and viral infections and autoimmune manifestations. MST1-deficient T cells poorly expressed the transcription factor FOXO1, the IL-7 receptor, and BCL2. Conversely, FAS expression and the FAS-mediating apoptotic pathway were up-regulated. These abnormalities suggest that increased cell death of naive and proliferating T cells is the main mechanism underlying this novel immunodeficiency. Our results characterize a new mechanism in primary T-cell immunodeficiencies and highlight a role of the MST1/FOXO1 pathway in controlling the death of human naive T cells.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2011-09-378364