CXCL12 Mediates Aberrant Costimulation of B Lymphocytes in Warts, Hypogammaglobulinemia, Infections, Myelokathexis Immunodeficiency

Giuliana Roselli, Elisa Martini, Vassilios Lougaris, Raffaele Badolato, Antonella Viola, Marinos Kallikourdis

Research output: Contribution to journalArticle

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Abstract

The Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is an immunodeficiency caused by mutations in chemokine receptor CXCR4. WHIM patient adaptive immunity defects remain largely unexplained. We have previously shown that WHIM-mutant T cells form unstable immunological synapses, affecting T cell activation. Here, we show that, in WHIM patients and WHIM CXCR4 knock-in mice, B cells are more apoptosis prone. Intriguingly, WHIM-mutant B cells were also characterized by spontaneous activation. Searching for a mechanistic explanation for these observations, we uncovered a novel costimulatory effect of CXCL12, the CXCR4 ligand, on WHIM-mutant but not wild-type B cells. The WHIM CXCR4-mediated costimulation led to increased B-cell activation, possibly involving mTOR, albeit without concurrently promoting survival. A reduction in antigenic load during immunization in the mouse was able to circumvent the adaptive immunity defects. These results suggest that WHIM-mutant CXCR4 may lead to spontaneous aberrant B-cell activation, via CXCL12-mediated costimulation, impairing B-cell survival and thus possibly contributing to the WHIM syndrome defects in adaptive immunity.

Original languageEnglish
Pages (from-to)1068
JournalFrontiers in Immunology
Volume8
DOIs
Publication statusPublished - 2017

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B-Lymphocytes
Adaptive Immunity
Immunological Synapses
WHIM syndrome
T-Lymphocytes
Chemokine Receptors
Immunization
Cell Survival
Apoptosis
Ligands
Mutation
Survival

Keywords

  • Journal Article

Cite this

CXCL12 Mediates Aberrant Costimulation of B Lymphocytes in Warts, Hypogammaglobulinemia, Infections, Myelokathexis Immunodeficiency. / Roselli, Giuliana; Martini, Elisa; Lougaris, Vassilios; Badolato, Raffaele; Viola, Antonella; Kallikourdis, Marinos.

In: Frontiers in Immunology, Vol. 8, 2017, p. 1068.

Research output: Contribution to journalArticle

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abstract = "The Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is an immunodeficiency caused by mutations in chemokine receptor CXCR4. WHIM patient adaptive immunity defects remain largely unexplained. We have previously shown that WHIM-mutant T cells form unstable immunological synapses, affecting T cell activation. Here, we show that, in WHIM patients and WHIM CXCR4 knock-in mice, B cells are more apoptosis prone. Intriguingly, WHIM-mutant B cells were also characterized by spontaneous activation. Searching for a mechanistic explanation for these observations, we uncovered a novel costimulatory effect of CXCL12, the CXCR4 ligand, on WHIM-mutant but not wild-type B cells. The WHIM CXCR4-mediated costimulation led to increased B-cell activation, possibly involving mTOR, albeit without concurrently promoting survival. A reduction in antigenic load during immunization in the mouse was able to circumvent the adaptive immunity defects. These results suggest that WHIM-mutant CXCR4 may lead to spontaneous aberrant B-cell activation, via CXCL12-mediated costimulation, impairing B-cell survival and thus possibly contributing to the WHIM syndrome defects in adaptive immunity.",
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AU - Badolato, Raffaele

AU - Viola, Antonella

AU - Kallikourdis, Marinos

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AB - The Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is an immunodeficiency caused by mutations in chemokine receptor CXCR4. WHIM patient adaptive immunity defects remain largely unexplained. We have previously shown that WHIM-mutant T cells form unstable immunological synapses, affecting T cell activation. Here, we show that, in WHIM patients and WHIM CXCR4 knock-in mice, B cells are more apoptosis prone. Intriguingly, WHIM-mutant B cells were also characterized by spontaneous activation. Searching for a mechanistic explanation for these observations, we uncovered a novel costimulatory effect of CXCL12, the CXCR4 ligand, on WHIM-mutant but not wild-type B cells. The WHIM CXCR4-mediated costimulation led to increased B-cell activation, possibly involving mTOR, albeit without concurrently promoting survival. A reduction in antigenic load during immunization in the mouse was able to circumvent the adaptive immunity defects. These results suggest that WHIM-mutant CXCR4 may lead to spontaneous aberrant B-cell activation, via CXCL12-mediated costimulation, impairing B-cell survival and thus possibly contributing to the WHIM syndrome defects in adaptive immunity.

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