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Defective thymic output in WAS patients is associated with abnormal actin organization

Li, Wenyan, Sun, Xiaoyu, Wang, Jinzhi, Zhao, Qin, Dai, Rongxin, Wang, Yanping, Zhou, Lina, Westerberg, Lisa, Ding, Yuan, Zhao, Xiaodong, Liu, Chaohong·2017·Scientific Reports
DOI 10.1038/s41598-017-12345-zPMC PMC5607224
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Abstract

Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeleton. Defective T - cell function is a major cause for immune deficiency in Wiskott-Aldrich syndrome (WAS) patients. T cells originate in the bone marrow and develop in the thymus, and then migrate to peripheral tissues. TCR excision circles (TRECs) present in thymic output cells stably, which is used as a molecular marker for thymic output. We found that CD8+ T naïve cells of classic WAS patients were significantly reduced, and TRECs in patients with classic WAS and X-linked thrombocytopenia (XLT) dramatically decreased compared with that of HCs. TRECs were also reduced in WAS (KO) mice. These suggest that defective thymic output partially accounts for T cell lymphopenia in WAS patients. However, the correlation between the defect of thymic output and actin organization still remains elusive. We found that the subcellular location and the levels of of F-actin were altered in T cells from both WAS and XLT patients compared to that of HCs with or without stimulation. Our study shows that WASp plays a critical role in thymic output, which highly correlates with the subcellular location and level of F-actin in T cells.

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Figure 1 WASp expression in XLT and WAS patients. (A) Flow cytometry analysis of the expression of WASp in PBMCs from normal control, WAS patient (P1) and XLT patient (P5). (B) The quantification of MFI of WASp from eight patients and healthy controls. (C) The age of WAS patients, XLT patients and their respective healthy controls.
Figure 1 WASp expression in XLT and WAS patients. (A) Flow cytometry analysis of the expression of WASp in PBMCs from normal control, WAS patient (P1) and XLT patient (P5). (B) The quantification of MFI of WASp from eight patients and healthy controls. (C) The age of WAS patients, XLT patients and their respective healthy controls.CC BY · PubMed Central
Figure 2 CD4+ and CD8+ T naïve cells are reduced in XLT and WAS patients. Flow cytometric analysis of CD3+ T - cell subsets in peripheral blood. (A) Flow cytometric analysis of CD3+ T - cell subsets in a healthy control. (B) Flow cytometric analysis of CD3+ T - cell subsets in P1. (C) Flow cytometric analysis of CD3+ T - cell subsets in P5. (D) Percentage and number of CD4+ T cells in WAS patients (P1-4), XLT patients (P5-8) and age-matched HCs (WAS-HC1, XLT-HC2). (E) Percentage and number of CD8+ T cells in WAS patients (P1-4), XLT patients (P5-8) and age-matched HCs (HC1, HC2). (F) Percentage and number of CD4 naïve T cells (CD4+CD27+CD45RA+) in WAS patients (P1-4), XLT patients (P5-8) and age-matched HCs (HC1, HC2). (G) Percentage and number of CD8 naïve T cells (CD4+CD27+CD45RA+) in WAS patients (P1-4), XLT patients (P5-8) and age-matched HCs (HC1, HC2).
Figure 2 CD4+ and CD8+ T naïve cells are reduced in XLT and WAS patients. Flow cytometric analysis of CD3+ T - cell subsets in peripheral blood. (A) Flow cytometric analysis of CD3+ T - cell subsets in a healthy control. (B) Flow cytometric analysis of CD3+ T - cell subsets in P1. (C) Flow cytometric analysis of CD3+ T - cell subsets in P5. (D) Percentage and number of CD4+ T cells in WAS patients (P1-4), XLT patients (P5-8) and age-matched HCs (WAS-HC1, XLT-HC2). (E) Percentage and number of CD8+ T cells in WAS patients (P1-4), XLT patients (P5-8) and age-matched HCs (HC1, HC2). (F) Percentage and number of CD4 naïve T cells (CD4+CD27+CD45RA+) in WAS patients (P1-4), XLT patients (P5-8) and age-matched HCs (HC1, HC2). (G) Percentage and number of CD8 naïve T cells (CD4+CD27+CD45RA+) in WAS patients (P1-4), XLT patients (P5-8) and age-matched HCs (HC1, HC2).CC BY · PubMed Central
Figure 3 sjTRECs is reduced in WASp deficient T cells. (A) Copy numbers of sjTRECs per 1 × 105 CD3+ T cells from HCs, WAS (P1-4) and XLT (P5-7) and (B) from WT and WAS KO mice.
Figure 3 sjTRECs is reduced in WASp deficient T cells. (A) Copy numbers of sjTRECs per 1 × 105 CD3+ T cells from HCs, WAS (P1-4) and XLT (P5-7) and (B) from WT and WAS KO mice.CC BY · PubMed Central
Figure 4 Actin organization is altered in XLT and WAS patients. (A) Sorted CD4+ T cells from HC, XLT and WAS patients were stained with phalloidin and antibodies specific for pWASP after stimulation with PMA and Ionomycin. Representative images from WAS patients and XLT patients are shown. (B and C) The quantification of MFI or TFI of actin on the membrane and in the cytoplasm from 100 T cells evenly of 5 HC1s, 5 HC2s, 4 XLT and 4 WAS patients. (D) 3D images of T cells stained with pWASP and phalloidin without stimulation from bottom and side view. (E) Quantification of the TFI of actin in each slice of T cells from a representative of HCs, XLT (P5) and WAS patients (P1). (F) Flow cytometry analysis of the MFI of F-actin of T cells upon stimulation with PMA and Ionomycin from 5 HC1s, 5 HC2s, 4 XLT and 4 WAS patients. Scale bar, 0.25 um. *P < 0.01.
Figure 4 Actin organization is altered in XLT and WAS patients. (A) Sorted CD4+ T cells from HC, XLT and WAS patients were stained with phalloidin and antibodies specific for pWASP after stimulation with PMA and Ionomycin. Representative images from WAS patients and XLT patients are shown. (B and C) The quantification of MFI or TFI of actin on the membrane and in the cytoplasm from 100 T cells evenly of 5 HC1s, 5 HC2s, 4 XLT and 4 WAS patients. (D) 3D images of T cells stained with pWASP and phalloidin without stimulation from bottom and side view. (E) Quantification of the TFI of actin in each slice of T cells from a representative of HCs, XLT (P5) and WAS patients (P1). (F) Flow cytometry analysis of the MFI of F-actin of T cells upon stimulation with PMA and Ionomycin from 5 HC1s, 5 HC2s, 4 XLT and 4 WAS patients. Scale bar, 0.25 um. *P < 0.01.CC BY · PubMed Central

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Research works printed but not linked: 22

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Metadata

Authors
Li, W., Sun, X., Wang, J., Zhao, Q., Dai, R., Wang, Y., Zhou, L., Westerberg, L., Ding, Y., Zhao, X., & Liu, C.
ORCID
Westerberg, Lisa
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-09-20
Volume
7
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-017-12345-z
PMC
PMC5607224
Cited by
9
References
0
Language
en
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CoChat. (2026). Citation check: Defective thymic output in WAS patients is associated with abnormal actin organization. https://app.cochat.ai/papers/10.1038/s41598-017-12345-z
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Li, W., Sun, X., Wang, J., Zhao, Q., Dai, R., Wang, Y., Zhou, L., Westerberg, L., Ding, Y., Zhao, X., & Liu, C. (2017). Defective thymic output in WAS patients is associated with abnormal actin organization. Scientific Reports. https://doi.org/10.1038/s41598-017-12345-z