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

  1. Nadine T. Nehme1,2,
  2. Jana Pachlopnik Schmid1,2,
  3. Franck Debeurme1,2,
  4. Isabelle André-Schmutz1,2,
  5. Annick Lim3,
  6. Patrick Nitschke4,
  7. Frédéric Rieux-Laucat1,2,
  8. Patrick Lutz5,
  9. Capucine Picard2,68,*,
  10. Nizar Mahlaoui2,8,*,
  11. Alain Fischer1,2,8,*, and
  12. Geneviève de Saint Basile1,2,6,8,*
  1. 1Inserm U768, Paris, France;
  2. 2Université Paris Descartes, Sorbone Paris Cité, Faculté de Médecine, Necker Hospital, Paris, France;
  3. 3Inserm U668 and Lymphocyte Development Unit, Institut Pasteur, Paris, France;
  4. 4Service de Bioinformatique, Université Paris Descartes, Paris, France;
  5. 5Unité d'Hématologie Pédiatrique, Hôpital de Hautepierre, Strasbourg, France;
  6. 6Centre d'Etudes des Déficits Immunitaires, Assistance Publique–Hôpitaux de Paris (AP-HP) Hôpital Necker, Paris, France;
  7. 7Inserm U980, Necker Medical Schoool, Paris, France; and
  8. 8AP-HP Hôpital Necker-Enfants Malades, Pediatric Immuno-Hematology Unit and National Referral Center for Primary Immune Deficiencies, Paris, France

Abstract

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.

  • Submitted September 9, 2011.
  • Accepted November 29, 2011.
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