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


CONCLUSIONS
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.
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
Sara
S
Trifari
Samantha
S
Scaramuzza
Marco
M
Catucci
Maurilio
M
Ponzoni
Luca
L
Mollica
Robert
R
Chiesa
Federica
F
Cattaneo
Fanny
F
Lafouresse
Ronan
R
Calvez
William
W
Vermi
Daniela
D
Medicina
Maria Carmina
MC
Castiello
Francesco
F
Marangoni
Marita
M
Bosticardo
Claudio
C
Doglioni
Maurizio
M
Caniglia
Alessandro
A
Aiuti
Anna
A
Villa
Maria-Grazia
MG
Roncarolo
Loïc
L
Dupré
D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D002469:Cell Separation; D004252:DNA Mutational Analysis; D005434:Flow Cytometry; D006801:Humans; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology*; D008297:Male; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009030:Mosaicism; D009154:Mutation; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics* / Q000276:immunology*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics*
D051316:Wiskott-Aldrich Syndrome Protein