Blood-borne soluble protein antigen intensifies T cell activation in autoimmune CNS lesions and exacerbates clinical disease.
We explored the effect of i.v. soluble antigen on autoaggressive, myelin basic protein-specific effector T cells within their target organ during acute experimental autoimmune encephalomyelitis (EAE). Intravital two-photon imaging revealed that i.v. autoantigen reached the CNS and was taken up and processed by antigen-presenting cells within 30 min after injection. The exogenous autoantigen dramatically changed the motility and function of autoreactive effector T cells within the EAE lesions: T cells that had been cruising through the tissue slowed down and became tethered to local antigen-presenting cells within 1 h. One hour later, the effector T cells massively produced proinflammatory cytokines and up-regulated membranous activation markers. This strong activation of the T cells boosted CNS inflammation and aggravated clinical disease. Postactivated effector and resting memory T cells specific for a non-CNS antigen (ovalbumin) were recruited to EAE lesions and moved there without contacting antigen-presenting cells. These cells were similarly arrested and activated after i.v. infusion of ovalbumin, and they also exacerbated clinical disease. Our data are relevant for autoantigen-based therapies of autoimmune disorders. Further, the study indicates how brain unrelated antigens (microbial components) leaking into the chronically inflamed CNS through the bloodstream might trigger relapses in multiple sclerosis.
Odoardi
F
F
Max Planck Institute for Neurobiology, 82152 Martinsried, Germany.
Kawakami
N
N
Klinkert
W E F
WE
Wekerle
H
H
Flügel
A
A
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001798:Blood Proteins / Q000276:immunology*; D002470:Cell Survival; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D007156:Immunologic Memory / Q000276:immunology; D007275:Injections, Intravenous; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology*; D051381:Rats; D012995:Solubility; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D000941:Antigens; D001798:Blood Proteins