Pertussis Toxin Signals through the TCR to Initiate Cross-Desensitization of the Chemokine Receptor CXCR4

Abstract

Pertussis toxin (PTx) has been shown to exert a variety of effects on immune cells independent of its ability to ADP-ribosylate G proteins. Of these effects, the binding subunit of PTx (PTxB) has been shown to block signaling via the chemokine receptor CCR5, but the mechanism involved in this process is unknown. Here, we show that PTxB causes desensitization of a related chemokine receptor, CXCR4, and explore the mechanism by which this occurs. CXCR4 is the receptor for the chemokine stromal cell-derived factor 1α (SDF-1α) and elicits a number of biological effects, including stimulation of T cell migration. PTxB treatment causes a decrease in CXCR4 surface expression, inhibits G protein-associated signaling, and blocks SDF-1α-mediated chemotaxis. We show that PTxB mediates these effects by activating the TCR signaling network, as the effects are dependent on TCR and ZAP70 expression. Additionally, the activation of the TCR with anti-CD3 mAb elicits a similar set of effects on CXCR4 activity, supporting the idea that TCR signaling leads to cross-desensitization of CXCR4. The inhibition of CXCR4 by PTxB is rapid and transient; however, the catalytic activity of PTx prevents CXCR4 signaling in the long term. Thus, the effects of PTx holotoxin on CXCR4 signaling can be divided into two phases: short term by the B subunit, and long term by the catalytic subunit. These data suggest that TCR crosstalk with CXCR4 is likely a normal cellular process that leads to cross-desensitization, which is exploited by the B subunit of PTx.

The B Subunit of an AB5 Toxin Produced by Salmonella enterica Serovar Typhi Up-Regulates Chemokines, Cytokines, and Adhesion Molecules in Human Macrophage, Colonic Epithelial, and Brain Microvascular Endothelial Cell Lines

“…Some of these effects are dependent on the ADP-ribosyltransferase activity of the respective A subunit, but significant immunomodulation effects, particularly in lymphocytes, can also be elicited either by mutant holotoxins devoid of catalytic activity or by purified B subunit pentamers (16)(17)(18)(19). For CtxB and LTB, effects include altered antigen processing and presentation by macrophages, induction of cytokine secretion by monocytes, stimulation of proliferation of B and CD4 ϩ T cells, and induction of apoptosis in CD8 ϩ T cells (17).…”

Attenuated Bordetella pertussis Vaccine Candidate BPZE1 Promotes Human Dendritic Cell CCL21-Induced Migration and Drives a Th1/Th17 Response

“…PT has been known to prevent chemokine receptor signaling through the enzymatic activity of the A subunit (23,24). More recent studies revealed a novel mechanism by which PT may affect migration of T lymphocytes via the B subunit, which is mediated by interaction with the TCR (25). This process leads to desensitization of CXCR4; it occurs within a few minutes and it is reversible.…”

“…Furthermore, it has been shown that the Boligomer of PT might inhibit chemokine receptor signaling (25). We have hypothesized that the PT expressed by the virulent BPSM strain may impair chemotaxis of MDDCs and that BPZE1-treated MDDCs were allowed to migrate due to the PT detoxification.…”

Differential IL‐10 production by DCs determines the distinct adjuvant effects of LPS and PTX in EAE induction

“…MS is characterized by inflammation, demyelination, and axonal pathology and is thought to occur in genetically predisposed individuals following exposure to an environmental trigger that activates myelin-specific pathogenic T cells that can cross the blood-brain barrier. EAE is surface expression, inhibits G protein associated signaling, and blocks stromal cell derived factor 1 alpha mediated chemotaxis by activating the TCR signaling network [4]. However, the detailed mechanism by which PTX blocks CCR5 is unclear, although receptor crosstalk between an unknown PTX receptor and chemokine receptors has been suggested [4].…”

“…2014. 44: 1352-1362 Cellular immune response 1353 surface expression, inhibits G protein associated signaling, and blocks stromal cell derived factor 1 alpha mediated chemotaxis by activating the TCR signaling network [4]. However, the detailed mechanism by which PTX blocks CCR5 is unclear, although receptor crosstalk between an unknown PTX receptor and chemokine receptors has been suggested [4].…”