T-cell receptor diversity is selectively skewed in T-cell populations of patients with Wiskott-Aldrich syndrome

Background: Wiskott-Aldrich syndrome (WAS) is a severe disorder characterized by thrombocytopenia, eczema, immunodeficiency, and increased risk of autoimmune disease and lymphoid malignancies. The immunodeficiency caused by a lack of WAS protein expression has been mainly attributed to defective T-cell functions. Whether WAS mutations differentially influence the T-cell receptor (TCR) diversity of different T-cell subsets is unknown. Objective: We aimed to identify the degree and pattern of skewing in the variable region of the TCR b-chain (Vb) in different T-cell subsets from patients with WAS. Methods: The TCR repertoire diversity in total peripheral T cells, sorted CD4 1 and CD8 1 T cells, and CD45RA 1 (CD45RA 1 CD45RO 2 cells) and CD45RO 1 (CD45RA 2 CD45RO 1 cells) CD4 1 and CD8 1 T cells from patients with WAS and age-matched healthy control subjects was analyzed and compared by using spectratyping of complementarity-determining region 3. The complementaritydetermining region 3 of TCRb transcripts in CD45RA 1 CD4 1 and CD45RA 1 CD8 1 T cells, CD45RO 1 CD4 1 T cells, CD8 1 terminally differentiated effector memory T (Temra) cells, and naive CD8 1 T cells (CD8 1 CD45RO 2 CCR7 1 cells) from patients and control subjects were analyzed and compared by using high-throughput sequencing. Results: The TCR repertoire diversity in CD45RO 1 CD4 1 T cells and CD8 1 Temra cells of patients with WAS was significantly skewed in comparison with that seen in agematched control subjects. Conclusion: Our results indicate that WAS gene mutations selectively influence TCR repertoire development or expansion in CD45RO 1 (memory) CD4 1 T cells.