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Pertussis Toxin Signals through the TCR to Initiate Cross-Desensitization of the Chemokine Receptor CXCR4¹

Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267

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 1 (SDF-1) 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-1-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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R56 AI023695 (to A.A.W. and W.E.M.) and by start-up funds from the University of Cincinnati (to W.E.M.). A.A.W. acknowledges support from the Epidemiology and Surveillance Division in the National Immunization Program at the Centers for Disease Control and Prevention. O.D.S. was supported by a National Institutes of Health Training Grant T32 AI055406.

² Address correspondence and reprint requests to Dr. William E. Miller, Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, 2256 Medical Science Building, 231 Albert Sabin Way, Cincinnati, OH 45267. E-mail address: william.miller{at}uc.edu

³ Abbreviations used in this paper: SDF-1, stromal cell-derived factor 1; GRK2, G protein-coupled receptor kinase 2; PKC, protein kinase C; PTx, pertussis toxin; WT, wild type.