IFN-gamma-induced chemokines synergize with pertussis toxin to promote T cell entry to the central nervous system.
Inflammation of the CNS, which occurs during multiple sclerosis and experimental autoimmune encephalomyelitis, is characterized by increased levels of IFN-gamma, a cytokine not normally expressed in the CNS. To investigate the role of IFN-gamma in CNS, we used intrathecal injection of a replication-defective adenovirus encoding murine IFN-gamma (AdIFNgamma) to IFN-gamma-deficient (GKO) mice. This method resulted in stable, long-lived expression of IFN-gamma that could be detected in cerebrospinal fluid using ELISA and Luminex bead immunoassay. IFN-gamma induced expression in the CNS of message and protein for the chemokines CXCL10 and CCL5, to levels comparable to those seen during experimental autoimmune encephalomyelitis. Other chemokines (CXCL2, CCL2, CCL3) were not induced. Mice lacking the IFN-gammaR showed no response, and a control viral vector did not induce chemokine expression. Chemokine expression was predominantly localized to meningeal and ependymal cells, and was also seen in astrocytes and microglia. IFN-gamma-induced chemokine expression did not lead to inflammation. However, when pertussis toxin was given i.p. to mice infected with the IFN-gamma vector, there was a dramatic increase in the number of T lymphocytes detected in the CNS by flow cytometry. This increase in blood-derived immune cells in the CNS did not occur with pertussis toxin alone, and did not manifest as histologically detectable inflammatory pathology. These results show that IFN-gamma induces a characteristic glial chemokine response that by itself is insufficient to promote inflammation, and that IFN-gamma-induced CNS chemoattractant signals can synergize with a peripheral infectious stimulus to drive T cell entry into the CNS.
Millward
Jason M
JM
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Caruso
Maria
M
Campbell
Iain L
IL
Gauldie
Jack
J
Owens
Trevor
T
D000818:Animals; D002465:Cell Movement; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology*; D018925:Chemokines / Q000032:analysis / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000276:immunology; D037342:Pertussis Toxin / Q000276:immunology / Q000494:pharmacology; D017471:Receptors, Interferon / Q000235:genetics; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D000096743:Interferon gamma Receptor
D018925:Chemokines; D007371:Interferon-gamma; D037342:Pertussis Toxin; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor