The WHIM (Warts, Hypogammaglobulinemia, Infections and 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 patient 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 immunological synapses between T cells and antigen presenting cells (APC). 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 due to impaired recruitment of the mutant receptor to the immunological 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.

The CXCR4 mutations in WHIM syndrome impair the stability of the T cell immunological synapse / M. Kallikourdis, A.E. Trovato, F. Anselmi, A. Sarukhan, G. Roselli, L. Tassone, R. Badolato, A. Viola. - In: BLOOD. - ISSN 0006-4971. - 122:5(2013 Aug 01), pp. 666-673. [10.1182/blood-2012-10-461830]

The CXCR4 mutations in WHIM syndrome impair the stability of the T cell immunological synapse

M. Kallikourdis
Primo
;
A.E. Trovato;A. Viola
Ultimo
2013-08-01

Abstract

The WHIM (Warts, Hypogammaglobulinemia, Infections and 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 patient 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 immunological synapses between T cells and antigen presenting cells (APC). 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 due to impaired recruitment of the mutant receptor to the immunological 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.
T cell ; WHIM ; immunological synapse
Settore MED/04 - Patologia Generale
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/221917
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