Publications

Abstract

BACKGROUND: The actin-interacting protein WDR1 promotes cofilin-dependent actin filament turnover. Biallelic WDR1 mutations have recently been identified in an immunodeficiency/autoinflammatory syndrome with aberrant morphology and function of myeloid cells. OBJECTIVE: Given the pleiotropic expression of WDR1, we here investigated to what extent it might control the lymphoid arm of the immune system in humans. METHODS: Histological and detailed immunological analyses were performed to elucidate the role of WDR1 in development and function of B and T lymphocytes. RESULTS: We here identified novel homozygous and compound heterozygous WDR1 missense mutations in six patients belonging to three 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 T follicular helper subset. However, peripheral T cells from the patients accumulated atypical actin structures at the immunological synapse and displayed reduced calcium flux and mildly impaired proliferation upon TCR 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 upon BCR/TLR stimulation. CONCLUSION: Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during the formation of the B-cell and T-cell immunological synapses.