Generation of a protective T-cell response following coronavirus infection of the central nervous system is not dependent on IL-12/23 signaling.
The functional role of IL-12 and IL-23 in host defense and disease following viral infection of the CNS was determined. Instillation of mouse hepatitis virus (MHV, a positive-strand RNA virus) into the CNS of mice results in acute encephalitis followed by a chronic immune-mediated demyelinating disease. Antibody-mediated blocking of either IL-23 (anti-IL-23p19) or IL-12 and IL-23 (anti-IL-12/23p40) signaling did not mute T-cell trafficking into the CNS or antiviral effector responses and mice were able to control viral replication within the brain. Therapeutic administration of either anti-IL-23p19 or anti-IL-12/23p40 to mice with viral-induced demyelination did not attenuate T-cell or macrophage infiltration into the CNS nor improve clinical disease or diminish white matter damage. In contrast, treatment of mice with anti-IL-12/23p40 or anti-IL-23p19 resulted in inhibition of the autoimmune model of demyelination, experimental autoimmune encephalomyelitis (EAE). These data indicate that (1) IL-12 and IL-23 signaling are dispensable in generating a protective T-cell response following CNS infection with MHV, and (2) IL-12 and IL-23 do not contribute to demyelination in a model independent of autoimmune T-cell-mediated pathology. Therefore, therapeutic targeting of IL-12 and/or IL-23 for the treatment of autoimmune diseases may offer unique advantages by reducing disease severity without muting protective responses following viral infection.
Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, USA.
Katherine S
KS
Held
William G
WG
Glass
Yevgeniya I
YI
Orlovsky
Kimberly A
KA
Shamberger
Ted D
TD
Petley
Patrick J
PJ
Branigan
Jill M
JM
Carton
Heena S
HS
Beck
Mark R
MR
Cunningham
Jacqueline M
JM
Benson
Thomas E
TE
Lane
D000818:Animals; D001327:Autoimmune Diseases; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology; D018352:Coronavirus Infections / Q000276:immunology* / Q000473:pathology; D003711:Demyelinating Diseases / Q000276:immunology; D004679:Encephalomyelitis / Q000276:immunology; D005260:Female; D018664:Interleukin-12 / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology*; D051379:Mice; D006517:Murine hepatitis virus / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D053759:Interleukin-23; D018664:Interleukin-12