Pertussis toxin signals through the TCR to initiate cross-desensitization of the chemokine receptor CXCR4.
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 1alpha (SDF-1alpha) 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-1alpha-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.
Schneider
Olivia D
OD
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Weiss
Alison A
AA
Miller
William E
WE
D000818:Animals; D001886:Bordetella pertussis / Q000276:immunology / Q000472:pathogenicity; D016466:CHO Cells; D020134:Catalytic Domain / Q000276:immunology; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003888:Desensitization, Immunologic; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D037342:Pertussis Toxin / Q000502:physiology*; D020239:Receptor Cross-Talk / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*
C527276:CXCR4 protein, human; D011948:Receptors, Antigen, T-Cell; D019718:Receptors, CXCR4; D037342:Pertussis Toxin