Pertussis toxin inhibits induction of tissue-specific autoimmune disease by disrupting G protein-coupled signals

Pertussis toxin (PTX) has been used for many years as an adjuvant that prom otes development of tissue-specific experimental autoimmune diseases such a s experimental autoimmune encephalomyelitis, experimental autoimmune uveiti s (EAU), and others. Enhancement of vascular permeability and of Th1 respon ses have been implicated in this effect. Here we report a surprising observ ation that, in a primed system, PTX can completely block the development of EAU. Disease was induced in B10.RIII mice by adoptive transfer of uveitoge nic T cells, or by immunization with a uveitogenic peptide. A single inject ion of PTX concurrently with infusion of the uveitogenic T cells, or two in jections 7 and 10 days after active immunization, completely blocked develo pment of EAU. EAU also was prevented by a 1-h incubation in vitro of the uv eitogenic T cells with PTX before infusing them into recipients. Uveitogeni c T cells treated with PTX in vitro and lymphoid cells from mice treated wi th PTX in vivo failed to migrate to chemokines in a standard chemotaxis ass ay. Neither the isolated B-oligomer subunit of PTX that lacks ADP ribosyltr ansferase activity nor the related cholera toxin that ADP-ribosylates G(s) (but not G(i)) proteins blocked EAU induction or migration to chemokines. W e conclude that PTX present at the time of cell migration to the target org an prevents EAU, and propose that it does so at least in part by disrupting signaling through G(i) protein-coupled receptors. Thus, the net effect of PTX on autoimmune disease would represent an integration of enhancing and i nhibitory effects.