Junfeng Wu1, Dawei Liu1, Wenwei Tu2, Wenxia Song3, Xiaodong Zhao4. 1. Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. 2. Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China. 3. Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Md. 4. Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. Electronic address: zhaoxd530@aliyun.com.
Abstract
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 β-chain (Vβ) in different T-cell subsets from patients with WAS. METHODS: The TCR repertoire diversity in total peripheral T cells, sorted CD4(+) and CD8(+) T cells, and CD45RA(+) (CD45RA(+)CD45RO(-) cells) and CD45RO(+) (CD45RA(-)CD45RO(+) cells) CD4(+) and CD8(+) 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 complementarity-determining region 3 of TCRβ transcripts in CD45RA(+)CD4(+) and CD45RA(+)CD8(+) T cells, CD45RO(+)CD4(+) T cells, CD8(+) terminally differentiated effector memory T (Temra) cells, and naive CD8(+) T cells (CD8(+)CD45RO(-)CCR7(+) cells) from patients and control subjects were analyzed and compared by using high-throughput sequencing. RESULTS: The TCR repertoire diversity in CD45RO(+)CD4(+) T cells and CD8(+) Temra cells of patients with WAS was significantly skewed in comparison with that seen in age-matched control subjects. CONCLUSION: Our results indicate that WAS gene mutations selectively influence TCR repertoire development or expansion in CD45RO(+) (memory) CD4(+) T cells.
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 β-chain (Vβ) in different T-cell subsets from patients with WAS. METHODS: The TCR repertoire diversity in total peripheral T cells, sorted CD4(+) and CD8(+) T cells, and CD45RA(+) (CD45RA(+)CD45RO(-) cells) and CD45RO(+) (CD45RA(-)CD45RO(+) cells) CD4(+) and CD8(+) 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 complementarity-determining region 3 of TCRβ transcripts in CD45RA(+)CD4(+) and CD45RA(+)CD8(+) T cells, CD45RO(+)CD4(+) T cells, CD8(+) terminally differentiated effector memory T (Temra) cells, and naive CD8(+) T cells (CD8(+)CD45RO(-)CCR7(+) cells) from patients and control subjects were analyzed and compared by using high-throughput sequencing. RESULTS: The TCR repertoire diversity in CD45RO(+)CD4(+) T cells and CD8(+) Temra cells of patients with WAS was significantly skewed in comparison with that seen in age-matched control subjects. CONCLUSION: Our results indicate that WAS gene mutations selectively influence TCR repertoire development or expansion in CD45RO(+) (memory) CD4(+) T cells.
Authors: Yu Nee Lee; Francesco Frugoni; Kerry Dobbs; Irit Tirosh; Likun Du; Francesca A Ververs; Heng Ru; Lisa Ott de Bruin; Mehdi Adeli; Jacob H Bleesing; David Buchbinder; Manish J Butte; Caterina Cancrini; Karin Chen; Sharon Choo; Reem A Elfeky; Andrea Finocchi; Ramsay L Fuleihan; Andrew R Gennery; Dalia H El-Ghoneimy; Lauren A Henderson; Waleed Al-Herz; Elham Hossny; Robert P Nelson; Sung-Yun Pai; Niraj C Patel; Shereen M Reda; Pere Soler-Palacin; Raz Somech; Paolo Palma; Hao Wu; Silvia Giliani; Jolan E Walter; Luigi D Notarangelo Journal: Sci Immunol Date: 2016-12-16