A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT.
In studies using genetically deficient mice, a role for the lymphotoxin (LT) system in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) has remained controversial. Here, we have reassessed this conclusion by using a fusion protein decoy that blocks the LT pathway in vivo without evoking the developmental defects inherent in LT-deficient mice. We have found that inhibition of the LT pathway prevented disease in two models of EAE that do not rely on the administration of pertussis toxin. Surprisingly, disease attenuation was due to specific blockade of LTalphabeta binding rather than the binding of LIGHT to its receptors. In a third system that requires pertussis toxin, LT inhibition did not affect disease, as was observed when the same model was used with LT-deficient mice. Disease prevention in pertussis toxin-free models was associated with defects in T cell responses and migration. When the DO11.10 T cell transgenic system was used, inhibition of the LT pathway was shown to uncouple T cell priming from T cell recall responses. Therefore, it is hypothesized that the LT pathway and its ability to maintain lymphoid microenvironments is critical for sustaining late-phase T cell responses in multiple sclerosis.
Gommerman
Jennifer L
JL
Department of Exploratory Sciences, Cambridge, Massachusetts, USA. jen.gommerman@utoronto.ca.
Giza
Keith
K
Perper
Stuart
S
Sizing
Irene
I
Ngam-Ek
Apinya
A
Nickerson-Nutter
Cheryl
C
Browning
Jeffrey L
JL
D000818:Animals; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology*; D005260:Female; D007962:Leukocytes / Q000502:physiology; D008233:Lymphotoxin-alpha / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D008233:Lymphotoxin-alpha; D008565:Membrane Proteins; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha