title: The CXCR4 mutations in WHIM syndrome impair the stability of the T-cell immunologic synapse.
abstract: WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome is a rare disease characterized by diverse symptoms indicative of aberrantly functioning immunity. It is caused by mutations in the chemokine receptor CXCR4, which impair its intracellular trafficking, leading to increased responsiveness to chemokine ligand and retention of neutrophils in bone marrow. Yet WHIM symptoms related to adaptive immunity, such as delayed IgG switching and impaired memory B-cell function, remain largely unexplained. We hypothesized that the WHIM-associated mutations in CXCR4 may affect the formation of immunologic synapses between T cells and antigen-presenting cells (APCs). We show that, in the presence of competing external chemokine signals, the stability of T-APC conjugates from patients with WHIM-mutant CXCR4 is disrupted as a result of impaired recruitment of the mutant receptor to the immunologic synapse. Using retrogenic mice that develop WHIM-mutant T cells, we show that WHIM-mutant CXCR4 inhibits the formation of long-lasting T-APC interactions in ex vivo lymph node slice time-lapse microscopy. These findings demonstrate that chemokine receptors can affect T-APC synapse stability and allow us to propose a novel mechanism that contributes to the adaptive immune response defects in WHIM patients.
authors.affiliation: Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Marinos
authors.initials: M
authors.lastname: Kallikourdis
authors.forename: Anna Elisa
authors.initials: AE
authors.lastname: Trovato
authors.forename: Fabio
authors.initials: F
authors.lastname: Anselmi
authors.forename: Adelaida
authors.initials: A
authors.lastname: Sarukhan
authors.forename: Giuliana
authors.initials: G
authors.lastname: Roselli
authors.forename: Laura
authors.initials: L
authors.lastname: Tassone
authors.forename: Raffaele
authors.initials: R
authors.lastname: Badolato
authors.forename: Antonella
authors.initials: A
authors.lastname: Viola
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D054992:Immunological Synapses / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D000081207:Primary Immunodeficiency Diseases; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014860:Warts / Q000235:genetics*
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4