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.

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.

Key words: Primary immunodeficiency, Wiskott-Aldrich syndrome, secondary mutation

Abbreviations used: aa, Amino acid, HD, Healthy donor, NK, Natural killer, TCR, T-cell receptor, WAS, Wiskott-Aldrich syndrome, WASP, Wiskott-Aldrich syndrome protein, wt, Wild-type