期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 142, 期 5, 页码 1589-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2018.04.023
关键词
WD repeat-containing protein 1; actin cytoskeleton; immunodeficiency; lymphocytes; immunologic synapse
资金
- Vienna Science and Technology Fund [WWTF-LS16-060, WWTF-LS14-31]
- Austrian Science Fund [I2250-B28]
- French National Agency for Research [ANR-13-BSV1-0031]
- ZonMW Vidi grant [91712323]
- National Health and Medical Research Council of Australia
- Austrian Science Fund (FWF) [I2250] Funding Source: Austrian Science Fund (FWF)
Background: The actin-interacting protein WD repeat-containing protein 1 (WDR1) promotes cofilin-dependent actin filament turnover. Biallelic WDR1 mutations have been identified recently in an immunodeficiency/autoinflammatory syndrome with aberrant morphology and function of myeloid cells. Objective: Given the pleiotropic expression of WDR1, here we investigated to what extent it might control the lymphoid arm of the immune system in human subjects. Methods: Histologic and detailed immunologic analyses were performed to elucidate the role of WDR1 in the development and function of B and T lymphocytes. Results: Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis. In addition to defective adhesion and motility of neutrophils and monocytes, WDR1 deficiency was associated with aberrant T-cell activation and B-cell development. T lymphocytes appeared to develop normally in the patients, except for the follicular helper T-cell subset. However, peripheral T cells from the patients accumulated atypical actin structures at the immunologic synapse and displayed reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation. WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased apoptosis on B-cell receptor/Toll-like receptor stimulation. Conclusion: Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during formation of the B-cell and T-cell immunologic synapses.
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