Revertant T lymphocytes in a patient with Wiskott-Aldrich syndrome: Analysis of function and distribution in lymphoid organs

Sara Trifari, Samantha Scaramuzza, Marco Catucci, Maurilio Ponzoni, Luca Mollica, Robert Chiesa, Federica Cattaneo, Fanny Lafouresse, Ronan Calvez, William Vermi, Daniela Medicina, Maria Carmina Castiello, Francesco Marangoni, Marita Bosticardo, Claudio Doglioni, Maurizio Caniglia, Alessandro Aiuti, Anna Villa, Maria Grazia Roncarolo, Loïc Dupré

Research output: Contribution to journalArticlepeer-review


Background: The Wiskott-Aldrich syndrome (WAS) is a rare genetic disease characterized by thrombocytopenia, immunodeficiency, autoimmunity, and hematologic malignancies. Secondary mutations leading to re-expression of WAS protein (WASP) are relatively frequent in patients with WAS. Objective: The tissue distribution and function of revertant cells were investigated in a novel case of WAS gene secondary mutation. Methods: A vast combination of approaches was used to characterize the second-site mutation, to investigate revertant cell function, and to track their distribution over a 18-year clinical follow-up. Results: The WAS gene secondary mutation was a 4-nucleotide insertion, 4 nucleotides downstream of the original deletion. This somatic mutation allowed the T-cell-restricted expression of a stable, full-length WASP with a 3-amino acid change compared with the wild-type protein. WASP + T cells appeared early in the spleen (age 10 years) and were highly enriched in a mesenteric lymph node at a later time (age 23 years). Revertant T cells had a diversified T-cell-receptor repertoire and displayed in vitro and in vivo selective advantage. They proliferated and produced cytokines normally on T-cell-receptor stimulation. Consistently, the revertant WASP correctly localized to the immunologic synapse and to the leading edge of migrating T cells. Conclusion: Despite the high proportion of functional revertant T cells, the patient still has severe infections and autoimmune disorders, suggesting that re-expression of WASP in T cells is not sufficient to normalize immune functions fully in patients with WAS.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Issue number2
Publication statusPublished - Feb 2010


  • Primary immunodeficiency
  • secondary mutation
  • Wiskott-Aldrich syndrome

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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