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 promotes development of tissue-specific experimental autoimmune diseases such as experimental autoimmune encephalomyelitis, experimental autoimmune uveitis (EAU), and others. Enhancement of vascular permeability and of Th1 responses have been implicated in this effect. Here we report a surprising observation that, in a primed system, PTX can completely block the development of EAU. Disease was induced in B10.RIII mice by adoptive transfer of uveitogenic T cells, or by immunization with a uveitogenic peptide. A single injection of PTX concurrently with infusion of the uveitogenic T cells, or two injections 7 and 10 days after active immunization, completely blocked development of EAU. EAU also was prevented by a 1-h incubation in vitro of the uveitogenic T cells with PTX before infusing them into recipients. Uveitogenic T cells treated with PTX in vitro and lymphoid cells from mice treated with PTX in vivo failed to migrate to chemokines in a standard chemotaxis assay. Neither the isolated B-oligomer subunit of PTX that lacks ADP ribosyltransferase activity nor the related cholera toxin that ADP-ribosylates G(s) (but not G(i)) proteins blocked EAU induction or migration to chemokines. We conclude that PTX present at the time of cell migration to the target organ 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 inhibitory effects.
Su
S B
SB
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Silver
P B
PB
Zhang
M
M
Chan
C C
CC
Caspi
R R
RR
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000008:administration & dosage / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005500:Follow-Up Studies; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors* / Q000502:physiology; D007115:Immunization Schedule; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D007962:Leukocytes / Q000473:pathology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D009928:Organ Specificity / Q000276:immunology; D037342:Pertussis Toxin; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000637:transplantation; D014605:Uveitis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D010566:Virulence Factors, Bordetella / Q000008:administration & dosage* / Q000494:pharmacology
D018925:Chemokines; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D009687:Nuclear Proteins; D011956:Receptors, Cell Surface; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go