Impaired cytotoxic function and exhausted phenotype of natural killer cells in VEXAS syndrome
Abstract
Abstract VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an autoinflammatory disorder caused by acquired somatic ubiquitin like modifier activating enzyme 1 (UBA1) mutations in hematopoietic stem cells, affecting peripheral myeloid and natural killer (NK) cells. Given the high rate of severe infections in patients with VEXAS, we hypothesized that NK-cell dysfunction contributes to this susceptibility. We conducted a comprehensive immune characterization of peripheral NK cells in patients with VEXAS (n = 40), patients with autoinflammatory diseases without UBA1 mutations (n = 22), and older sex-matched healthy controls (n = 16). Multiparameter phenotyping used cytometry by time-of-flight, single-cell RNA sequencing (scRNA-seq), whole-blood stimulation assays, and in vitro NK-cell cytotoxic assay. Peripheral NK cells in VEXAS were quantitatively and qualitatively impaired. Mass cytometry revealed reduced frequencies of mature cytotoxic CD56dim NK cells and expansion of the CD56high CD16dim subset. NK cells exhibited exhaustion features, including increased programmed cell death protein 1 expression, and reduced cytotoxic markers such as NKp46 and CD8α. scRNA-seq analysis showed decreased signatures of cytotoxicity and interleukin-2 (IL-2) and interferon gamma (IFN-γ) production, alongside increased inflammatory signatures. Whole-blood stimulation assays confirmed impaired IL-2, IFN-γ, and granzyme B production following Toll-like receptor 3 (TLR3), TLR4, and TLR7/TLR8 agonist stimulation. Extended NK phenotyping by flow cytometry confirmed reduced activating receptors’ expression and impaired IFN-γ production in VEXAS syndrome. Moreover, in vitro UBA1 inhibitors impaired NK-cell cytotoxic capacity and promote cell death. Finally, reduced NK-cell frequencies were independently associated with an increased risk of severe infections. These findings suggest that NK-cell dysfunction in VEXAS syndrome contributes to increased susceptibility to severe infections.
Article Details
Authors (40)
Paul Breillat
1INSERM U970, Paris Centre de Recherche Cardiovasculaire, Université Paris Cité, Paris, France
Francesco Carbone
Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM U1163
Emilie Lereclus
Quentin Riller
8Université Paris Cité, Paris, France
Thibaut d'Izarny-Gargas
1Université de Paris Cité, INSERM, U970, Paris-Centre de Recherche Cardiovasculaire, Paris, France
Céline Posseme
10Translational Immunology Unit, Institut Pasteur, Université de Paris Cité, Paris, France
Marie Templé
11Université de Paris Cité, Institut Cochin, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, INSERM U1016, Paris, France
Lin-Pierre Zhao
Marine Luka
Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM U1163
Estibaliz Lazaro
Roderau Outh
Guillaume Le Guenno
6Médecine Interne, CHU Estaing, Clermont-Ferrand, France, Clermont-Ferrand, France
Francois Lifermann
Yannick Dieudonné
17Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases of Strasbourg, Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
Marie Berleur
20Department of Internal Medicine, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France
Cédric Lenormand
Department of Dermatology, Hôpital Civil, CHU de Strasbourg, Strasbourg, France
Karl Balabanian
Thierry Weitten
22Department of Internal Medicine, Centre Hospitalier Intercommunal des Alpes du Sud, Gap, France
Vivien Guillotin
23Department of Internal Medicine, Bordeaux University Hospital-Saint-André, Bordeaux, France
Marie Kostine
23Department of Internal Medicine, Bordeaux University Hospital-Saint-André, Bordeaux, France
Barbara Burroni
9CHU Cochin, Paris, France
Adrien Bigot
Alexandra Audemard-Verger
Aldric Manuel
26Department of Internal Medicine, Centre Hospitalier Annecy-Genevois, Annecy, France
Antoine Dossier
5Internal Medicine Department, Claude Bernard Bichat Hospital, APHP, Paris, France
Cécile Golden
28Department of Internal Medicine, Groupe Hospitalier de Haute-Saône, Vesoul, France
Jean-Philippe Martellosio
29Department of Internal Medicine, Centre Hospitalo Universitaire de Poitiers, Poitiers, France
Benoit Faucher
30Department of Internal Medicine, La Timone Hospital, Assistance Publique-Hôpitaux de Marseille, Marseille, France
Benjamin De Sainte Marie
30Department of Internal Medicine, La Timone Hospital, Assistance Publique-Hôpitaux de Marseille, Marseille, France
Nadine Magy-Bertrand
17Besançon University hospital, Besançon, France
Valentin Lacombe
Stéphane Vinzio
34Department of Internal Medicine, Groupe Hospitalier Mutualiste de Grenoble, Grenoble, France
Sylvie Grosleron
35Department of Internal Medicine, Centre Hospitalier Agen-Nérac, Agen, France
Léa Dionet
1INSERM U970, Paris Centre de Recherche Cardiovasculaire, Université Paris Cité, Paris, France
Pierre-Louis Tharaux
Darragh Duffy
Mickaël Ménager
Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM U1163
Nicolas Dulphy
Olivier Kosmider
11Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Institut Cochin, Université de Paris Cité, Paris, France
Benjamin Terrier
1INSERM U970, Paris Centre de Recherche Cardiovasculaire, Université Paris Cité, Paris, France