Mutations affecting the actin regulator WDR1 lead to aberrant lymphoid immunity

Publication date: Available online 8 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Laurène Pfajfer, Nina K. Mair, Raúl Jiménez-Heredia, Ferah Genel, Nesrin Gulez, Ömür Ardeniz, Birgit Hoeger, Sevgi Köstel Bal, Christoph Madritsch, Artem Kalinichenko, Rico Chandra Ardy, Bengü Gerçeker, Javier Rey-Barroso, Hanna Ijspeert, Stuart G. Tangye, Ingrid Simonitsch-Klupp, Johannes B. Huppa, Mirjam van der Burg, Loïc Dupré, Kaan Boztug
BackgroundThe 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.ObjectiveGiven the pleiotropic expression of WDR1, we here investigated to what extent it might control the lymphoid arm of the immune system in humans.MethodsHistological and detailed immunological analyses were performed to elucidate the role of WDR1 in development and function of B and T lymphocytes.ResultsWe 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.ConclusionOur 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.

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Capsule summary: Patients harboring biallelic WDR1 mutations present with a complex immunodeficiency characterized by functional defects of myeloid and lymphoid cells and therefore require clinical strategies to compensate for both defective innate and adaptive immunity.


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